elastin and Aortic-Aneurysm

Aortic aneurysm is a vascular disease whereby the ECM (extracellular matrix) of a blood vessel degenerates, leading to dilation and eventually vessel wall rupture. Recently, it was shown that calcification of the vessel wall is involved in both the initiation and progression of aneurysms. Changes in aortic wall structure that lead to aneurysm formation and vascular calcification are actively mediated by vascular smooth muscle cells. Vascular smooth muscle cells in a healthy vessel wall are termed contractile as they maintain vascular tone and remain quiescent. However, in pathological conditions they can dedifferentiate into a synthetic phenotype, whereby they secrete extracellular vesicles, proliferate, and migrate to repair injury. This process is called phenotypic switching and is often the first step in vascular pathology. Additionally, healthy vascular smooth muscle cells synthesize VKDPs (vitamin K-dependent proteins), which are involved in inhibition of vascular calcification. The metabolism of these proteins is known to be disrupted in vascular pathologies. In this review, we summarize the current literature on vascular smooth muscle cell phenotypic switching and vascular calcification in relation to aneurysm. Moreover, we address the role of vitamin K and VKDPs that are involved in vascular calcification and aneurysm. Visual Overview- An online visual overview is available for this article.

Topics: Aortic Aneurysm; Elastin; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Phenotype; Transforming Growth Factor beta; Vascular Calcification; Vitamin K; Vitamin K Epoxide Reductases

Once considered as inert, the extracellular matrix recently revealed to be biologically active. Elastin is one of the most important components of the extracellular matrix. Many vital organs including arteries, lungs and skin contain high amounts of elastin to assure their correct function. Physiologically, the organism contains a determined quantity of elastin from the early development which may remain physiologically constant due to its very long half-life and very low turnover. Taking into consideration the continuously ongoing challenges during life, there is a physiological degradation of elastin into elastin-derived peptides which is accentuated in several disease states such as obstructive pulmonary diseases, atherosclerosis and aortic aneurysm. These elastin-derived peptides have been shown to have various biological effects mediated through their interaction with their cognate receptor called elastin receptor complex eliciting several signal transduction pathways. In this review, we will describe the production and the biological effects of elastin-derived peptides in physiology and pathology.

Topics: Aortic Aneurysm; Atherosclerosis; Elastin; Extracellular Matrix; Humans; Lung Diseases, Obstructive; Peptide Fragments; Receptors, Cell Surface; Signal Transduction

This review discusses the role of biomarkers for both diagnoses and disease monitoring before, during, and after treatment of aortic dissection.

Topics: Aortic Aneurysm; Aortic Dissection; Biomarkers; C-Reactive Protein; Calcium-Binding Proteins; Calponins; Elastin; Endothelin-1; Fibrin Fibrinogen Degradation Products; Humans; Microfilament Proteins; Natriuretic Peptide, Brain; Peptide Fragments; Peptidyl-Dipeptidase A; Receptors, Notch; Smooth Muscle Myosins; Transforming Growth Factor beta

Functional and molecular aortic imaging has shown great promise for evaluation of aortic disease, and may soon augment conventional assessment of aortic dimensions for the clinical management of patients.. A range of imaging techniques is available for evaluation of patients with aortic disease. Magnetic resonance blood flow imaging can identify atherosclerosis prone aortic regions and may be useful for predicting aneurysm growth. Computational modeling can demonstrate significant differences in wall stress between abdominal aortic aneurysms of similar size and may better predict rupture than diameter alone. Metabolic imaging with fluorodeoxyglucose-PET [(FDG)-PET] can identify focal aortic wall inflammation that may portend rapid progression of disease. Molecular imaging with probes that target collagen and elastin can directly exhibit changes in the vessel wall associated with disease.. The complexity of aortic disease is more fully revealed with new functional imaging techniques than with conventional anatomic analysis alone. This may better inform surveillance imaging regimens, medical management and decisions regarding early intervention for aortic disease.

Topics: Aorta; Aortic Aneurysm; Collagen; Elastin; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Molecular Imaging; Positron-Emission Tomography; Radiopharmaceuticals

To review the strategies on repairing elastic fibers in aorta.. Literature concerning elastic fiber as well as its repairment was consulted and summarized from three aspects: enhancement of the expressions of its components, improvement of the condition of its assembly, and reduction of the destructive effects.. Elastin is concerned as the main protein to be enhanced with three different methods including gene transfection, stimulation with ectogenesis factors, and induction of phenotype transition of smooth muscle cell. Fibulin and lysyl oxidases show the ability to improve the assembly of the elastic fiber, while the related mechanisms are not clear. Matrix metalloproteinases are regarded as the main destructive factors, and researches focus on reducing their expression as well as their destructive effects.. To assure a high-quality repair of elastic fibers in aorta, their components should be sufficiently expressed and effectively assemblyed, and the destructive effects caused by dangerous factors should also be reduced.

Topics: Animals; Aorta; Aortic Aneurysm; Elastic Tissue; Elastin; Gene Expression Regulation; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Myocytes, Smooth Muscle; Protein-Lysine 6-Oxidase; Risk Factors; Transfection

Aortic aneurysm is common, accounting for 1-2% of all deaths in industrialized countries. Early theories of the causes of human aneurysm mostly focused on inherited or acquired defects in components of the extracellular matrix in the aorta. Although several mutations in the genes encoding extracellular matrix proteins have been recognized, more recent discoveries have shown important perturbations in cytokine signalling cascades and intracellular components of the smooth muscle contractile apparatus. The modelling of single-gene heritable aneurysm disorders in mice has shown unexpected involvement of the transforming growth factor-β cytokine pathway in aortic aneurysm, highlighting the potential for new therapeutic strategies.

Topics: Angiotensin II; Animals; Aortic Aneurysm; Disease Models, Animal; Elastin; Humans; Muscle, Smooth, Vascular; Transforming Growth Factor beta

Acute aortic dissection is a disease that is often a challenge to diagnose. Early and immediate diagnosis is important for initiation of treatment and improved survival. Despite recent advances in imaging methods to diagnose the disease, biochemical methods are not available.. Biomarkers that might be useful for the biochemical detection of acute aortic dissection have been recently described, such as assays for the circulating proteins, smooth muscle myosin heavy chain, creatine kinase BB-isozyme, calponin (smooth muscle troponin) and elastin. C-reactive protein and D-dimer have also been shown to be useful.. Biomarker-assisted diagnosis of acute aortic dissection would be helpful in detecting this acute catastrophic aortic disease, which still remains a challenge to diagnose. Although recent progress in development of biomarkers has been made, there is no widely accepted strategy. Available biomarkers such as D-dimer may play an assistive role in the meantime.

Topics: Algorithms; Aortic Aneurysm; Aortic Dissection; Biomarkers; C-Reactive Protein; Calcium-Binding Proteins; Calponins; Elastin; Fibrin Fibrinogen Degradation Products; Humans; Isoenzymes; Microfilament Proteins; Practice Guidelines as Topic; Transforming Growth Factor beta1

Acute aortic syndromes have an incidence of >30 per million per annum and a high mortality without definitive treatment. Survival may relate to the speed of diagnosis. Although pain is the most common symptom, there is a large fraction of patients in whom the diagnosis may be mistaken or overlooked. Currently, a high index of clinical suspicion is the chief prompt that diverts a patient into a definitive algorithm of imaging investigations. Although there is no point-of-care biochemical test that can be reliably used to positively identify dissection, biomarkers are available that could accelerate the diagnostic pathway and thereby expedite treatment.

Topics: Acute Disease; Animals; Aortic Aneurysm; Aortic Dissection; Biomarkers; C-Reactive Protein; Elastin; Humans; Myosin Heavy Chains

The approximately 4000 'normal' mammals that synthesize ascorbic acid produce on average circa 50 mg/kg per day routinely. Although humans have the same needs as normal mammals, they do not produce ascorbic acid at all and, on average, ingest only circa 1 mg/kg per day. The normal mammals' much larger production enables them to continually renew structural proteins, including both collagen, a flexible but inelastic tissue, and elastin, the elastic connective tissue. As a result, many normal mammals maintain a 'youthful' appearance with little gross anatomical change from age of maturity (i.e, first estrus) to more than 20 times age of maturity. In stark contrast, the extremely small ascorbic acid intake of humans does not enable them to maintain a youthful flexibility and elasticity beyond possibly 6 times age of maturity (most have died before 8 times). This loss of youthful qualities in structural proteins results in susceptibility for many forms of deterioration in both appearance and properties of vascular and other structural tissues. One such deterioration is aortic aneurysm, a common cause of morbidity and mortality. We hypothesize herein that improved dietary intake of essential nutrients needed to enhance the renewal of all structural proteins can: (1). prevent this deterioration completely; and (2). cure even large aortic aneurysms without surgery.

Topics: Animals; Aortic Aneurysm; Ascorbic Acid; Collagen; Elastic Tissue; Elastin; Female; Humans; Longevity; Male; Models, Cardiovascular

Experimental aortic aneurysm may be evoked in animals by application of chemical compounds disturbing biosynthesis, posttranslating modifications and degradation of elastin and collagen, local damage of the aortic wall by chemical, thermal and mechanical factors and by increased blood pressure. Administration of protease inhibitors, anti-inflammatory drugs, agents enhancing synthesis and formation of elastic and collagen fibers and hypotensive drugs prevent formation enlargement and rupture of aneurysm.

Topics: Aneurysm, Ruptured; Animals; Aortic Aneurysm; Collagen; Disease Models, Animal; Elastin; Hemodynamics; Proline

The incidence of abdominal aortic aneurysm has recently increased. There is still no accurate definition of abdominal aortic aneurysm. The diameter of abdominal aortic aneurysms is the only factor permitting evaluation of the risk of rupture of aneurysms whose growth remains unpredictable. Abdominal aortic aneurysm is a multi-factorial disease associated with aortic aging and atheroma. It differs from stenotic disease by the intensity of degenerative or destructive phenomena in the media. Particular hemodynamic conditions in the infrarenal abdominal aorta seem to enhance the development of aneurysm at this level. While certain constitutional anomalies of the extracellular matrix of proteins seem to enhance the development of abdominal aortic aneurysm, protease activity of as yet undetermined origin also seems to play a prominent role. Family cases of abdominal aortic aneurysms have been reported but the mechanisms responsible remain to be determined. Several genetic markers have been suggested. The most reliable marker of aortic aneurysm is arteriomegaly.

Topics: Aorta, Abdominal; Aortic Aneurysm; Collagen; Dilatation, Pathologic; Elastin; Humans

Topics: Abnormalities, Drug-Induced; Amino Acid Oxidoreductases; Aminopropionitrile; Aneurysm; Animals; Aortic Aneurysm; Blood Vessels; Bone and Bones; Bone Diseases; Cleft Palate; Collagen; Connective Tissue; Elastin; Fetus; Heart Defects, Congenital; Humans; Kyphosis; Lathyrism; Lysine; Neurologic Manifestations; Nitriles; Poultry Diseases; Rodent Diseases; Spinal Cord; Spinal Cord Diseases; Stomach; Turkeys

Information on the biomechanical properties of aortic root aneurysms that would facilitate our understanding of their rupture modes is currently unavailable. In this study, whole-thickness wall specimens from aortic root aneurysms were studied in vitro so as to compare the biomechanical properties with gross histomorphology and composition, in relation to age, region, and direction. The stress-strain relationship was determined under uniaxial loading conditions and characterized by the Fung-type material model in terms of optimized material constants; failure properties were recorded. The connective tissue contents of the basic scleroproteins were also determined through computerized histology. Aging had a deleterious influence on the tensile strength of the aneurysmal sinus tissue, causing also stiffening and reduced extensibility that was consistent with the deficient elastin and collagen contents. Direction-dependent differences were demonstrated in the noncoronary sinus, with the circumferential being stiffer and stronger than the longitudinal direction, justified by the preferred collagen reinforcement along that direction there. In the left and right coronary sinus, the material constants and failure properties were essentially the same in the two directions, justified by the arbitrary orientation of medial (collagen and elastin fibers, and cellular) components relative to the circumferential-longitudinal directions. The material characterization results afforded, and the regional and age-related differences in the strength of the sinus wall, i.e. in its capacity to withstand hemodynamic stresses, are hoped to provide novel insight into the pathophysiological mechanisms responsible for the highest incidence of ruptured aortic root aneurysms in the right coronary and noncoronary sinus.

Topics: Aging; Aortic Aneurysm; Aortic Rupture; Collagen; Elastin; Female; Humans; Male; Middle Aged; Sinus of Valsalva; Stress, Physiological

We aimed to establish an enzyme-linked immunosorbent assay for measuring soluble elastin fragments (sELAF) in serum and to reveal its usefulness in diagnosing acute aortic dissection (AAD).. An enzyme-linked immunosorbent assay to measure sELAF in serum was developed by using the newly created double monoclonal antibodies, which recognize the different epitopes of human aortic elastin. Twenty-five AAD patients, 50 patients with acute myocardial infarction (AMI), and 474 healthy individuals were enrolled in the study. The sELAF levels from healthy subjects gradually increased with aging. When the cutoff point for positivity was set at the mean+3 SD (ie, 3 SD above the mean in healthy subjects at each age), 16 AAD patients (64.0%) were found be positive, whereas only 1 AMI patient was found to be positive (2.0%). AAD patients with either an open or a partially open pseudolumen were found be 88.9% positive for sELAF, whereas those with its early closure were 0% positive. The difference in the sELAF levels between AAD patients with and without a thrombotic closure of false lumen was significant (60.3+/-15.6 versus 135.4+/-53.2 ng/mL, respectively; P<0.005).. The sELAF level in serum may be a useful marker for helping in the diagnosis and screening of AAD and may also help to distinguish AAD from AMI.

Topics: Acute Disease; Adult; Aged; Aortic Aneurysm; Aortic Dissection; Biomarkers; Case-Control Studies; Diagnosis, Differential; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Myocardial Infarction; Reference Values; Risk Factors

The leading cause of mortality in patients with Marfan syndrome (MFS) is thoracic aortic aneurysm and dissection. Notch signaling is essential for vessel morphogenesis and function. However, the role of Notch signaling in aortic pathology and aortic smooth muscle cell (SMC) differentiation in Marfan syndrome (MFS) is not completely understood.. RNA-sequencing on ascending aortic tissue from a mouse model of MFS,. The murine RNA-sequencing data were validated with mouse and human MFS aortic tissue, demonstrating elevated Notch3 activation in MFS. Data further revealed that upregulation and activation of Notch3 were concomitant with increased expression of SMC contractile markers. Inhibiting Notch3 activation with DAPT attenuated aortic enlargement and improved survival of. Our data demonstrated that matrix abnormalities in the aorta of MFS are associated with increased Notch3 activation. Enhanced Notch3 activation in MFS contributed to aortic aneurysm formation in MFS. This might be mediated by inducing a contractile phenotypic change of SMC. Our results suggest that inhibiting Notch3 activation may provide a strategy to prevent and treat aortic aneurysms in MFS.

Topics: Animals; Aorta; Aortic Aneurysm; Diamines; Disease Models, Animal; Elastin; Fibrillin-1; Humans; Marfan Syndrome; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Targeted Therapy; Myocytes, Smooth Muscle; Receptor, Notch3; Thiazoles

Fluoroquinolones are one of the most frequently prescribed antibiotics. However, their use increases the risk of Aortic aneurysm and dissection (AAD). The mechanism underlying this effect remains unclear. AAD are caused by weakening of the aortic wall and loss of vascular smooth muscle cells. Osteopontin is involved in the occurrence and development of AAD. The aim of the present study was to examine the role of moxifloxacin, a fluoroquinolone, in the occurrence of AAD using a moderate-severity AAD mouse model. Four-week-old male C57BL/6J mice were fed a high-fat diet. At 8 weeks of age, the mice were infused with saline or angiotensin II (1000 ng kg

Topics: Angiotensin II; Animals; Anti-Bacterial Agents; Aortic Aneurysm; Aortic Dissection; Disease Models, Animal; Elastin; Eosine Yellowish-(YS); Hematoxylin; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Moxifloxacin; Muscle Proteins; Myocytes, Smooth Muscle; Osteopontin; Rubber; Water

Fragile X syndrome (FXS) is an inherited genetic condition that is the leading known cause of inherited intellectual developmental disability. Phenotypically, individuals with FXS also present with distinct physical features including, elongated face, prominent ears, pectus excavatum, macroorchidism, and joint laxity, which suggests connective tissue dysplasia. In addition to mitral valve prolapse, aortic dilatation has been identified within individuals with FXS. Abnormal elastin fiber networks have been found in the skin, valves, and aorta in individual cases. Aortic dilatation has been described in other connective tissue disorders, particularly Marfan syndrome. However, while aortic aneurysms are characteristic of Marfan syndrome, no similar cases have been reported in FXS patients to date. This case report details the presentation of two patients with FXS and aortic aneurysm. Our two cases highlight the risks of aortic pathology in FXS, and the need for monitoring in asymptomatic patients with significant aortic dilatation.

Topics: Aortic Aneurysm; Connective Tissue Diseases; Elastin; Fragile X Syndrome; Humans; Marfan Syndrome; Mitral Valve Prolapse

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS.. Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+ mice challenged with Angiotensin II.. NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition.

Topics: Animals; Aortic Aneurysm; Aortic Aneurysm, Thoracic; Aortic Diseases; Disease Models, Animal; Elastin; Fibrillin-1; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Nitro Compounds; Oleic Acids

Although aortic root and ascending aortic aneurysms are treated the same, they differ in embryological development and pathological processes. This study examines the microscopic structural differences between aortic root and ascending aortic aneurysms, correlating these features to the macroscopic pathophysiological processes.. We obtained surgical samples from ascending aortic aneurysms (n = 11), aortic root aneurysms (n = 3), and non-aneurysmal patients (n = 7), Aortic collagen and elastin content were examined via histological analysis, and immunohistochemistry techniques used to determine collagen I, III, and IV subtypes. Analysis was via observational features, and colour deconvolution quantification techniques.. Elastin fiber disruption and fragmentation was the most extensive in the proximal aneurysmal regions. Medial fibrosis and collagen density increased in proximal aneurysmal regions and aortic root aneurysms (p < 0.005). Collagen I was seen in highest quantity in aortic root aneurysms. Collagen I content was greatest in the sinus tissue regions compared to the valvular and ostial regions (p < 0.005) Collagen III and IV quantification did not vary greatly. The most susceptible regions to ultrastructural changes in disease are the proximal ascending aorta and aortic root.. The aortic root differs histologically from the ascending aorta confirming its unique composition in aneurysm pathology. These findings should prompt further evaluation on the influence of this altered structure on function which could potentially guide clinical management.

Topics: Aorta; Aorta, Thoracic; Aortic Aneurysm; Aortic Aneurysm, Thoracic; Elastin; Humans

Aortic aneurysm is observed as a result of the extensive alteration in the elasticity of the aortic wall due to the breakdown of elastin and collagen. In this study, we studied the feasibility of scanning acoustic microscopy (SAM) and Raman spectroscopy (RS) in characterizing the dilated segments of the aorta from male and female patients with aortic aneurysm. SAM determined the acoustic property variation in the aorta by calculating the acoustic impedance values of aorta samples of 18 patients. RS determined the disease states by analyzing the chemical variation especially in the peaks related to elastin and collagen using the

Topics: Aorta; Aortic Aneurysm; Elastin; Female; Humans; Male; Microscopy, Acoustic; Spectrum Analysis, Raman

Marfan syndrome is one of the most common inherited disorders of connective tissue caused by fibrillin-1 mutations, characterized by enhanced transcription factor AP-1 DNA binding activity and subsequently abnormally increased expression and activity of matrix-metalloproteinases (MMPs). We aimed to establish a novel adeno-associated virus (AAV)-based strategy for long-term expression of an AP-1 neutralizing RNA hairpin (hp) decoy oligonucleotide (dON) in the aorta to prevent aortic elastolysis in a murine model of Marfan syndrome.. Using fibrillin-1 hypomorphic mice (mgR/mgR), aortic grafts from young (9 weeks old) donor mgR/mgR mice were transduced ex vivo with AAV vectors and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Grafts were explanted after 30 days. For in vitro studies, isolated primary aortic smooth muscle cells (SMCs) from mgR/mgR mice were used. Elastica-van-Giesson staining visualized elastolysis, reactive oxygen species (ROS) production was assessed using dihydroethidine staining. RNA F.I.S.H. verified AP-1 hp dON generation in the ex vivo transduced aortic tissue. MMP expression and activity were assessed by western blotting and immunoprecipitation combined with zymography.Transduction resulted in stable therapeutic dON expression in endothelial and SMCs. MMP expression and activity, ROS formation as well as expression of monocyte chemoattractant protein-1 were significantly reduced. Monocyte graft infiltration declined and the integrity of the elastin architecture was maintained. RNAseq analysis confirmed the beneficial effect of AP-1 neutralization on the pro-inflammatory environment in SMCs.. This novel approach protects from deterioration of aortic stability by sustained delivery of nucleic acids-based therapeutics and further elucidated how to interfere with the mechanism of elastolysis.

Topics: Animals; Aorta; Aortic Aneurysm; Cells, Cultured; Dependovirus; Dilatation, Pathologic; Disease Models, Animal; Elastin; Female; Fibrillin-1; Genetic Therapy; Genetic Vectors; Humans; Marfan Syndrome; Matrix Metalloproteinases; Mice, Transgenic; Oligonucleotides; Reactive Oxygen Species; Transcription Factor AP-1; Transduction, Genetic; Vascular Remodeling

Mechanical characteristics of both the healthy ascending aorta and acute type A aortic dissection were investigated using in vitro biaxial tensile tests, in vivo measurements via transoesophageal echocardiography and histological characterisations. This combination of analysis at tissular, structural and microstructural levels highlighted the following: (i) a linear mechanical response for the dissected intimomedial flap and, conversely, nonlinear behaviour for both healthy and dissected ascending aorta; all showed anisotropy; (ii) a stiffer mechanical response in the longitudinal than in the circumferential direction for the healthy ascending aorta, consistent with the histological quantification of collagen and elastin fibre density; (iii) a link between dissection and ascending aorta stiffening, as revealed by biaxial tensile tests. This result was corroborated by in vivo measurements with stiffness index, β, and Peterson modulus, E

Topics: Aged; Anisotropy; Aorta; Aortic Aneurysm; Aortic Dissection; Biomechanical Phenomena; Collagen; Echocardiography, Transesophageal; Elastin; Female; Humans; Male; Middle Aged; Stress, Mechanical; Tensile Strength

Growth of abdominal aortic aneurysms (AAA), localized aortal wall expansions, is driven by the disruption and subsequent loss of aortal wall elastic fibers by matrix metalloproteases (MMPs). Since elastic fibers do not naturally regenerate or repair, arresting/reversing AAA growth has not been possible. Previously, we showed utility of doxycycline (DOX), an MMP inhibitor drug, to stimulate elastic matrix neoassembly and crosslinking at low microgram per milliliter doses in addition to inhibiting MMPs. We currently show in aneurysmal smooth muscle cell (SMC) cultures that effects of exogenous DOX in this dose range are linked to its upregulation of transforming growth factor beta (TGF-β1) via its inhibition of the regulatory protein c-Jun-N-terminal kinase 2 (JNK 2). We have identified a DOX dose range that stimulates elastogenesis and crosslinking without adversely impacting cell viability. Using JNK 2 inhibition as a metric for pro-regenerative matrix effects of DOX, we further demonstrate that sustained, steady-state release of DOX at the useful dose, from poly(ethylene glycol)-poly(lactic glycolic acid) nanoparticles (NPs), provides pro-elastogenic and anti-proteolytic effects that could potentially be more pronounced than that of exogenous DOX. We attribute these outcomes to previously determined synergistic effects provided by cationic amphiphile groups functionalizing the polymer NP surface. Released DOX inhibited expression and phosphorylation of JNK to likely increase expression of TGF-β1, which is known to increase elastogenesis and lysyl oxidase-mediated crosslinking of elastic matrix. Our results suggest that JNK inhibition is a useful metric to assess pro-elastic matrix regenerative effects and point to the combinatorial regenerative benefits provided by DOX and cationic-functionalized NPs.

Topics: Animals; Aorta; Aortic Aneurysm; Cell Survival; Cells, Cultured; Doxycycline; Drug Liberation; Elastin; Male; MAP Kinase Kinase 4; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Myocytes, Smooth Muscle; Nanoparticles; Polyesters; Polyethylene Glycols; Rats, Sprague-Dawley; Regeneration; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1

The pathogenesis of aortic aneurysm (AA) is associated with chronic inflammation in the aortic wall with increased levels of matrix metalloproteinases (MMPs). Clarithromycin (CAM) has been reported to suppresses MMP activity. In this study, we investigated whether CAM could prevent the formation and rupture of AA.. Male apolipoprotein E-deficient mice (28-30 weeks of age) were infused with angiotensin II for 28 days. CAM (100 mg/kg/d) or saline (as a control) was administered orally to the mice every day (CAM group, n = 13; control group, n = 13). After the administration period, the aortic diameter, elastin content, macrophage infiltration, MMP levels, and levels of inflammatory cytokines, including nuclear factor κB (NF-κB), were measured.. The aortic diameter was significantly suppressed in the CAM group (P < .001). No rupture death was observed in the CAM group in contrast to five deaths (38%) in the control group (P < .01). CAM significantly suppressed the degradation of aortic elastin (56.3% vs 16.5%; P < .001) and decreased the infiltration of inflammatory macrophages (0.05 vs 0.16; P < .01). Compared with the controls, the enzymatic activity of MMP-2 and MMP-9 was significantly reduced in the CAM group (MMP-2, 0.15 vs 0.56 [P < .01]; MMP-9, 0.12 vs 0.60 [P < .01]), and the levels of interleukin 1β (346.6 vs 1066.0; P < .05), interleukin 6 (128.4 vs 346.2; P < .05), and phosphorylation of NF-κB were also decreased (0.3 vs 2.0; P < .01).. CAM suppressed the progression and rupture of AA through the suppression of inflammatory macrophage infiltration, a reduction in MMP-2 and MMP-9 activity, and the inhibition of elastin degradation associated with the suppression of NF-κB phosphorylation.

Topics: Administration, Oral; Angiotensin II; Animals; Aorta; Aortic Aneurysm; Aortic Rupture; Cells, Cultured; Clarithromycin; Disease Models, Animal; Elastin; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Macrophages; Male; Matrix Metalloproteinases, Secreted; Mice, Inbred C57BL; Mice, Knockout, ApoE; NF-kappa B; Phosphorylation; Vascular Remodeling

We have reported that nitrosonifedipine (NO-NIF), a photodegradation product of nifedipine, has strong antioxidant and endothelial protective effects, and can suppress several cardiovascular diseases in animal models. The objective of the present study was to investigate the effects of NO-NIF on aortic aneurysm formation.. The mice were infused with β-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. The oxidative stress was measured by dihydroethidium staining and nitrotyrosine staining. The expressions of inflammation-related genes were assessed by quantitative real-time PCR and immunohistochemical staining. To clarify the mechanisms of how NO-NIF suppresses vascular cell adhesion molecule (VCAM)-1, endothelial cells were used in in vitro system.. NO-NIF suppressed pharmacologically induced the aortic aneurysm formation and aortic expansion without blood pressure changes. NO-NIF suppressed elastin degradation and matrix metalloproteinase-2 mRNA expression. NO-NIF suppressed the reactive oxygen species-cyclophilin A positive feedback loop. Upregulated mRNA expressions of inflammation-related genes and endothelial VCAM-1 were suppressed by NO-NIF co-treatment in aortae.. NO-NIF has the potential to be a new, nifedipine-derived therapeutic drug for suppressing aortic aneurysm formation by directly improving aortic structure with its strong ability to reduce oxidative stress and inflammation.

Topics: Aminopropionitrile; Angiotensin II; Animals; Antigens, Differentiation; Antioxidants; Aortic Aneurysm; Chemokine CCL2; Cyclophilins; Disease Models, Animal; Elastin; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Male; Matrix Metalloproteinase 2; Mice; Nifedipine; Nitroso Compounds; Oxidative Stress; Photolysis; Reactive Oxygen Species; Vascular Cell Adhesion Molecule-1

Elastic fibers provide reversible elasticity to the large arteries and are assembled during development when hemodynamic forces are increasing. Mutations in elastic fiber genes are associated with cardiovascular disease. Mice lacking expression of the elastic fiber genes elastin ( Eln

Topics: Animals; Animals, Newborn; Aorta; Aortic Aneurysm; Arteries; Collagen Type VIII; Disease Models, Animal; Elastic Tissue; Elastin; Extracellular Matrix Proteins; Female; Gene Expression Regulation, Developmental; Insulin-Like Growth Factor Binding Protein 2; Joint Instability; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Protein-Lysine 6-Oxidase; Skin Diseases, Genetic; Thrombospondin 1; Vascular Malformations

Aortic root aneurysm formation and subsequent dissection and/or rupture remain the leading cause of death in patients with Marfan syndrome. Our laboratory has reported that miR-29b participates in aortic root/ascending aorta extracellular matrix remodeling during early aneurysm formation in

Topics: Animals; Aortic Aneurysm; Disease Models, Animal; Disease Progression; Echocardiography; Elastin; Extracellular Matrix; Female; Fetal Therapies; Genetic Therapy; Male; Marfan Syndrome; Matrix Metalloproteinases; Mice, Inbred C57BL; Mice, Mutant Strains; MicroRNAs; Molecular Targeted Therapy; Prenatal Care

To explore the role of microRNA (miR)-30a in the development of aortic dissection.. Human aortic specimens of aortic dissections and aneurysms were harvested. Aortic specimens from donors for heart transplantation served as controls. Rat aortic vascular smooth muscle cells (VSMCs) were transfected with agomiR-30a or antagomiR-30a, and control cells were incubated with empty vectors. Rats were pretreated with agomiR-30a or antagomiR-30a (5 × 10. Gene expression of miR-30a was much higher, and protein abundance of LOX and elastin was significantly lower, in the aortic dissection specimens (P < .05 vs controls). Transfection of agomiR-30a markedly decreased the luciferase activity of LOX in VSMCs of wild type, but not of LOX 3'-UTR mutant (P = .002). In cultured VSMCs, transfection of agomiR-30a dramatically enhanced the gene expression of miR-30a and down-regulated the protein abundance of LOX and elastin (P < .05 vs controls). Pretreatment with agomiR-30a in vivo enhanced miR-30a expression and down-regulated the protein abundance of LOX and elastin in rat aortas (P < .05 vs controls). The rate of dissection was significantly higher in rats pretreated with agomiR-30a (P = .003 vs controls).. Overexpression of miR-30a contributes to the development of aortic dissection, possibly by targeting LOX.

Topics: Animals; Aorta; Aortic Aneurysm; Aortic Dissection; Case-Control Studies; Cells, Cultured; Disease Models, Animal; Elastin; Gene Expression Regulation, Enzymologic; Humans; Male; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein-Lysine 6-Oxidase; Rats, Sprague-Dawley; Up-Regulation

Topics: Animals; Aorta; Aortic Aneurysm; Calcinosis; Elastin; Extracellular Signal-Regulated MAP Kinases; Humans; Marfan Syndrome; Mice; Mitogen-Activated Protein Kinase Kinases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle

Aneurysms of the ascending aorta are an outstanding challenge to clinicians as they may persist asymptomatic until they present with dissection or rupture. Intensive research is performed to reveal the molecular mechanisms causing aneurysm formation. Calpains are ubiquitous non-lysosomal cysteine proteases which are classically activated by calcium signaling. The two major forms of the calpain-family are calpain-I and calpain-II. Calpastatin specifically inhibits the proteolytic activity of calpain-I and -II. Recently it has been demonstrated in aneurysm tissues from ascending aortas obtained from Marfan syndrome patients that calpain-II expression is increased and calpastatin expression is decreased. Thus, we were interested in the probable role of calpains in aneurysms of ascending aorta in non-Marfan patients. Therefore, ascending aortic samples of dilated and non-dilated aortas were analyzed according to their calpain-I, -II and calpastatin content as well as the expression levels of MMPs and elastin as well as the infiltration of inflammatory cells. We have found significant differences in calpain-I and calpastatin protein expression and serum levels in patients with aneurysm of the ascending aorta. Furthermore, MMP-1 and MMP-3 expression levels correlate with calpain-I protein levels. Due to our findings we conclude that calpain-1 seems to be related to fibrotic alteration in aortic aneurysm tissue in our experimental group. The change in calpain-1 modulates the structure of aortic tissue causing alteration in elastin structure, thus enabling macrophage infiltration and elevation of MMP levels. Circulating levels of calpain-1 may be used as a prognostic marker in the future if further correlation analyses are done.

Topics: Aged; Aorta; Aortic Aneurysm; Calcium-Binding Proteins; Calpain; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunohistochemistry; Male; Metalloproteases; Middle Aged; Polymerase Chain Reaction

Aortic aneurysm is a life-threatening cardiovascular disorder caused by the predisposition for dissection and rupture. Genetic studies have proved the involvement of the transforming growth factor-β (TGF-β) pathway in aortic aneurysm. Smad4 is the central mediator of the canonical TGF-β signaling pathway. However, the exact role of Smad4 in smooth muscle cells (SMCs) leading to the pathogenesis of aortic aneurysms is largely unknown.. To determine the role of smooth muscle Smad4 in the pathogenesis of aortic aneurysms.. Conditional gene knockout strategy combined with histology and expression analysis showed that Smad4 or TGF-β receptor type II deficiency in SMCs led to the occurrence of aortic aneurysms along with an upregulation of cathepsin S and matrix metallopeptidase-12, which are proteases essential for elastin degradation. We further demonstrated a previously unknown downregulation of matrix metallopeptidase-12 by TGF-β in the aortic SMCs, which is largely abrogated in the absence of Smad4. Chemotactic assay and pharmacologic treatment demonstrated that Smad4-deficient SMCs directly triggered aortic wall inflammation via the excessive production of chemokines to recruit macrophages. Monocyte/macrophage depletion or blocking selective chemokine axis largely abrogated the progression of aortic aneurysm caused by Smad4 deficiency in SMCs.. The findings reveal that Smad4-dependent TGF-β signaling in SMCs protects against aortic aneurysm formation and dissection. The data also suggest important implications for novel therapeutic strategies to limit the progression of the aneurysm resulting from TGF-β signaling loss-of-function mutations.

Topics: Animals; Aorta; Aortic Aneurysm; Cathepsins; Cell Line; Chemokines; Chemotaxis; Elastin; Female; Genetic Predisposition to Disease; Macrophages; Male; Matrix Metalloproteinase 12; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Protein Serine-Threonine Kinases; Proteolysis; Rats; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA Interference; Smad4 Protein; Time Factors; Transfection; Up-Regulation

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1(C1039G/+) MFS mouse model.. Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal-regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent.. Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS.

Topics: Active Transport, Cell Nucleus; Animals; Aorta; Aortic Aneurysm; Apoptosis; Cells, Cultured; Cellular Senescence; Dilatation, Pathologic; Disease Models, Animal; Elastin; Female; Fibrillin-1; Genetic Predisposition to Disease; Human Umbilical Vein Endothelial Cells; Humans; Male; Marfan Syndrome; Mice, Inbred C57BL; Mice, Mutant Strains; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Sirtuin 1; Stilbenes

Aortic aneurysm is a disastrous vascular disease with high morbidity and mortality. Matrix metalloproteinases (MMPs), especially MMP-9, is implicated in the development of aortic aneurysm, but the effective MMP inhibitors are far from development. To develop new candidate compound for aortic aneurysm therapy, we evaluated the effects of salvianolic acid C (SalC) against the formation of aortic aneurysm.. Aortic aneurysm was induced by implantation of angiotension II (AngII) minipump in apolipoprotein E-deficient (ApoE. SalC significantly ameliorated the progression of aortic aneurysm in ApoE

Topics: Alkenes; Animals; Aorta; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Apolipoproteins E; Elastin; Gene Deletion; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice, Inbred C57BL; Polyphenols

Previous reports have shown that serum elastin fragments (SEFs) may be a useful biomarker for the diagnosis of an acute aortic dissection (AAD). However, because the reference interval of SEFs has not been established, it has not been determined whether SEFs are really useful for the diagnosis of AAD. The purpose of this study was to determine the usefulness of measuring SEFs for the diagnosis of AAD. A total of 42 consecutive patients aged 68 ± 18 years who were diagnosed with an AAD were studied. Patient background and SEF levels were examined on admission. SEF levels were also measured in patients undergoing a medical examination (n = 531, age 54 ± 17 years) to compare with those with an AAD. In the control group, SEF levels increased with age (R = 0.725, p <0.001). Then, we defined the upper limit of the reference interval of SEF levels as the 97.5th percentile of control SEF grouped by decade of life from the sixth to ninth decade. The overall risk of AAD exceeding the upper limit of the reference interval at each decade was 10% (4 of 42). For patients in their 60s and 70s, median SEF levels in the AAD group (89 [77 to 104], 93 [60 to 123] ng/ml, respectively) were not significantly higher than those in the control group (79 [68 to 92], 90 [79 to 106] ng/ml, respectively; p = 0.081 and 0.990, respectively). Our data suggest that measuring SEF levels may not be useful in the diagnosis of an AAD as the upper limit of the reference interval of the SEF level was unexpectedly higher.

Topics: Acute Disease; Aged; Aortic Aneurysm; Aortic Dissection; Biomarkers; Diagnosis, Differential; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged

Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3

Topics: Aneurysm; Animals; Aortic Aneurysm; Cell Proliferation; Connective Tissue; Disease Models, Animal; Echocardiography; Elastin; Extracellular Signal-Regulated MAP Kinases; Female; Immunohistochemistry; Inflammation; Male; Matrix Metalloproteinases; Mice; Mice, Knockout; Models, Biological; Molecular Imaging; Mortality; Muscle, Smooth, Vascular; Signal Transduction; Smad2 Protein; Smad3 Protein; Transcriptional Activation; Transforming Growth Factor beta; X-Ray Microtomography

Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome.. Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs.. Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.

Topics: Animals; Aorta; Aortic Aneurysm; Apoptosis; Autoradiography; Caspase Inhibitors; Caspases; Cell Membrane; Cells, Cultured; Disease Models, Animal; Disease Progression; Elastin; Female; Fibrillin-1; Fibrillins; Fluorescent Antibody Technique; Male; Marfan Syndrome; Mice, Inbred C57BL; Mice, Mutant Strains; Microfilament Proteins; Microscopy, Electron, Scanning; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Time Factors; Tomography, Emission-Computed, Single-Photon; Vascular Remodeling

Low-density lipoprotein receptor-related protein 1 (LRP1), a multifunctional protein involved in endocytosis and cell signaling pathways, leads to several vascular pathologies when deleted in vascular smooth muscle cells (SMCs). The purpose of this study was to determine whether LRP1 deletion in SMCs influenced angiotensin II-induced arterial pathologies.. LRP1 protein abundance was equivalent in selected arterial regions, but SMC-specific LRP1 depletion had no effect on abdominal and ascending aortic diameters in young mice. To determine the effects of LRP1 deficiency on angiotensin II vascular responses, SMC-specific LRP1 (smLRP1(+/+)) and smLRP1-deficient (smLRP1(-/-)) mice were infused with saline, angiotensin II, or norepinephrine. Several smLRP(-/-) mice died of superior mesenteric arterial (SMA) rupture during angiotensin II infusion. In surviving mice, angiotensin II profoundly augmented SMA dilation in smLRP1(-/-) mice. SMA dilation was blood pressure dependent as demonstrated by a similar response during norepinephrine infusion. SMA dilation was also associated with profound macrophage accumulation, but minimal elastin fragmentation. Angiotensin II infusion led to no significant differences in abdominal aorta diameters between smLRP1(+/+) and smLRP1(-/-) mice. In contrast, ascending aortic dilation was exacerbated markedly in angiotensin II-infused smLRP1(-/-) mice, but norepinephrine had no significant effect on either aortic region. Ascending aortas of smLRP1(-/-) mice infused with angiotensin II had minimal macrophage accumulation but significantly increased elastin fragmentation and mRNA abundance of several LRP1 ligands including MMP-2 (matrix metalloproteinase-2) and uPA (urokinase plasminogen activator).. smLRP1 deficiency had no effect on angiotensin II-induced abdominal aortic aneurysm formation. Conversely, angiotensin II infusion in smLRP1(-/-) mice exacerbated SMA and ascending aorta dilation. Dilation in these 2 regions had differential association with blood pressure and divergent pathological characteristics.

Topics: Aneurysm; Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Arterial Pressure; Cells, Cultured; Dilatation, Pathologic; Disease Models, Animal; Elastin; Gene Deletion; Ligands; Low Density Lipoprotein Receptor-Related Protein-1; Macrophages; Male; Matrix Metalloproteinase 2; Mesenteric Artery, Superior; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Norepinephrine; Receptors, LDL; RNA, Messenger; Tumor Suppressor Proteins; Urokinase-Type Plasminogen Activator

Degradation and fragmentation of elastic fibers in the media dilate the aortic wall excessively in patients with acute Stanford type A aortic dissection (AD). Such dilatation occurs not via aortic stiffening, which is diagnosed using imaging under physiological loading, but due to the abovementioned intrinsic changes in elastic fibers, which can be detected at the low-stress region of the stress-strain relationship. Our objective is to determine an age-related correlation between distensibility and histology. We conducted uniaxial stretching tests and a histological evaluation of the ascending aorta (AA) using AD samples obtained at surgery from 9 elderly patients (aged 52-85 yr), with no heritable connective tissue disorders, and control (CN) samples from 10 subjects at autopsy (aged 56-86 yr). We compared the distensibility, or an increase in strain for the uniaxial tensile stress of 0-50 kPa, between the AD and CN groups, and correlated it with age and histology. Distensibility was significantly greater in the AD than that in the CN group (p=0.030), but elastin content was significantly lower (p=0.0025). The positive correlation between distensibility and elastin content in CN samples suggests that the distensibility increases with elastic fiber histological abnormalities. The age-matched collagen content decreased with the age of the patients, and did not differ between the AD and CN groups. The age-matched distensibility in the AD and CN groups decreased and became closer with aging. Such intrinsic properties should be considered during imaging to assess distensibility in patients with AD.

Topics: Aged; Aged, 80 and over; Aorta; Aortic Aneurysm; Aortic Dissection; Biomechanical Phenomena; Case-Control Studies; Collagen; Elasticity; Elastin; Female; Humans; Male; Middle Aged

Sirtuin-1 (SirT1), a nicotinamide adenine dinucleotide(+)-dependent deacetylase, is a key enzyme in the cellular response to metabolic, inflammatory, and oxidative stresses; however, the role of endogenous SirT1 in the vasculature has not been fully elucidated. Our goal was to evaluate the role of vascular smooth muscle SirT1 in the physiological response of the aortic wall to angiotensin II, a potent hypertrophic, oxidant, and inflammatory stimulus.. Mice lacking SirT1 in vascular smooth muscle (ie, smooth muscle SirT1 knockout) had drastically high mortality (70%) caused by aortic dissection after angiotensin II infusion (1 mg/kg per day) but not after an equipotent dose of norepinephrine, despite comparable blood pressure increases. Smooth muscle SirT1 knockout mice did not show any abnormal aortic morphology or blood pressure compared with wild-type littermates. Nonetheless, in response to angiotensin II, aortas from smooth muscle SirT1 knockout mice had severely disorganized elastic lamellae with frequent elastin breaks, increased oxidant production, and aortic stiffness compared with angiotensin II-treated wild-type mice. Matrix metalloproteinase expression and activity were increased in the aortas of angiotensin II-treated smooth muscle SirT1 knockout mice and were prevented in mice overexpressing SirT1 in vascular smooth muscle or with use of the oxidant scavenger tempol.. Endogenous SirT1 in aortic smooth muscle is required to maintain the structural integrity of the aortic wall in response to oxidant and inflammatory stimuli, at least in part, by suppressing oxidant-induced matrix metalloproteinase activity. SirT1 activators could potentially be a novel therapeutic approach to prevent aortic dissection and rupture in patients at risk, such as those with hypertension or genetic disorders, such as Marfan's syndrome.

Topics: Angiotensin II; Animals; Aorta, Thoracic; Aortic Aneurysm; Aortic Dissection; Cells, Cultured; Cyclic N-Oxides; Disease Models, Animal; Elastic Tissue; Elastin; Free Radical Scavengers; Hypertension; Matrix Metalloproteinases; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Sirtuin 1; Spin Labels; Time Factors

The pathogenesis of non-familial, sporadic ascending aortic aneurysms (SAAA) is poorly understood, and the relationship between ascending aortic atherosclerosis and medial degeneration is unclear. We evaluated the prevalence and severity of aortic atherosclerosis and its association with medial degeneration in SAAA.. Atherosclerosis was characterized in ascending aortic tissues collected from 68 SAAA patients (mean age, 62.9 ± 12.0 years) and 15 controls (mean age, 56.6 ± 11.4 years [P = 0.07]) by using a modified American Heart Association classification system. Upon histologic examination, 97% of SAAA patients and 73% of controls showed atherosclerotic changes. Most SAAA samples had intermediate (types 2 and 3, 35%) or advanced atherosclerosis (types ≥ 4; 40%), whereas most control samples showed minimal atherosclerosis (none or type 1, 80%; P < 0.001 after adjusting for age). In a separate analysis, we examined the total incidence and grade distribution of medial degenerative changes among SAAA samples according to atherosclerosis grade. Advanced atherosclerosis was associated with higher grades of smooth muscle cell depletion (P < 0.001), elastic fiber depletion (P = 0.02), elastic fiber fragmentation (P < 0.001), and mucopolysaccharide accumulation (P = 0.04). Aortic diameter was larger in SAAA patients with advanced atherosclerosis than in patients with minimal (P = 0.04) or intermediate atherosclerosis (P = 0.04). Immunostaining showed marked CD3+ T-cell and CD68+ macrophage infiltration, MMP-2 and MMP-9 production, and cryopyrin expression in the medial layer adjacent to atherosclerotic plaque.. SAAA tissues exhibited advanced atherosclerosis that was associated with severe medial degeneration and increased aortic diameter. Our findings suggest a role for atherosclerosis in the progression of sporadic ascending aortic aneurysms.

Topics: Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aorta; Aortic Aneurysm; Atherosclerosis; Case-Control Studies; CD3 Complex; Disease Progression; Elastic Tissue; Elastin; Female; Glycosaminoglycans; Humans; Male; Middle Aged; Myocytes, Smooth Muscle

An aortic aneurysm (AA) is caused by atherosclerosis with chronic inflammation. Mesenchymal stem cells (MSCs) have potential anti-inflammatory properties. In this study, we examined whether an already-formed AA can be treated by intravenous injection of bone marrow-derived (BM)-MSCs in a mouse model.. AA was induced in apolipoprotein E-deficient mice by angiotensin II-infusion for 28 days through sub-cutaneous osmotic mini-pumps. After that, 1 × 10(6) BM-MSCs (in 0.2 ml saline) or 0.2 ml saline as a control was injected via the tail vein. Mice were sacrificed at 2 (saline group n = 10, BM-MSC group n = 10), 4 (saline group n = 6, BM-MSC group n = 7) or 8 weeks (saline group n = 5, BM-MSC group n = 6) after injection. The aortic tissues of each group were dissected. Aortic diameter, elastin content, matrix metalloproteinase (MMP)-2 and -9 enzymatic activity and cytokine concentrations were measured, as was macrophage infiltration, which was also evaluated histologically.. The incidence of AA in the BM-MSC group was reduced at 2 weeks (BM-MSC 40% vs saline 100%, P < 0.05), and aortic diameter was reduced at 2 and 4 weeks (2 weeks: 1.40 vs 2.29 mm, P < 0.001; 4 weeks: 1.73 vs 2.32 mm, P < 0.05). The enzymatic activities of MMP-2 and -9 were reduced in the BM-MSC group at 2 weeks (active-MMP-2: 0.28 vs 0.45 unit/ml, P < 0.05; active-MMP-9: 0.16 vs 0.34 unit/ml, P < 0.05). Inflammatory cytokines were down-regulated in the BM-MSC group (interleukin-6: 2 weeks: 1475.6 vs 3399.5 pg/ml, P < 0.05; 4 weeks: 2184.7 vs 3712.8 pg/ml, P < 0.05 and monocyte chemotactic protein-1: 2 weeks: 208.0 vs 352.7 pg/ml, P < 0.05) and insulin-like growth factor (IGF)-1 and tissue inhibitor of metalloproteinase (TIMP)-2 were up-regulated in the BM-MSC group at 2 weeks (IGF-1: 4.7 vs 2.0 ng/ml, P < 0.05; TIMP-2: 9.5 vs 4.0 ng/ml, P < 0.001). BM-MSC injection inhibited infiltration of M1 macrophages and preserved the construction of elastin.. Our results suggest that BM-MSCs might be an effective treatment for AA. Further investigation is necessary to optimize the injected dosage and the frequency of BM-MSCs to prevent a transient effect.

Topics: Administration, Intravenous; Animals; Aorta; Aortic Aneurysm; Bone Marrow Transplantation; Disease Models, Animal; Elastin; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenchymal Stem Cell Transplantation; Mice; Mice, Transgenic

Energy loss is a biomechanical parameter that represents the relative amount of energy absorbed by the aorta during the cardiac cycle. We aimed to correlate energy loss with ascending aortic aneurysm size and histopathologic findings to elucidate the pathophysiology of aneurysm complications.. Aneurysmal ascending aortic specimens were obtained during surgery. Control specimens were obtained from autopsy and organ donors. Biaxial tensile tests were performed on the 4 quadrants of the aortic ring. Energy loss was calculated using the integral of the stress-strain curve during loading and unloading. It was compared with the size and the traditional biomechanical parameter, stiffness (apparent modulus of elasticity). Elastin, collagen, and mucopolysaccharide content were quantified using Movat pentachrome staining of histology slides.. A total of 41 aortas were collected (34 aneurysmal, 7 control). The aneurysms exhibited increased stiffness (P < .0001) and energy loss (P < .0001) compared with the controls. Energy loss correlated significantly with aortic size (P < .0001, r(2) = .60). A hinge point was noted at a diameter of 5.5 cm, after which energy loss increased rapidly. The relationship between energy loss and size became strongly linear once the size was indexed to the body surface area (P < .0001, r(2) = .78). Energy loss correlated with the histopathologic findings, especially the collagen/elastin ratio (P = .0002, r(2) = .49). High energy loss distinguished patients with pathologic histologic findings from others with similar diameters.. As ascending aortas dilate, they exhibit greater energy loss that rapidly increases after 5.5 cm. This mirrors the increase in complications at this size. Energy loss correlates with imbalances in elastin and collagen composition, suggesting a measurable link between the histopathologic features and mechanical function.

Topics: Adult; Aged; Aorta; Aortic Aneurysm; Biomechanical Phenomena; Case-Control Studies; Collagen; Dilatation, Pathologic; Elastic Modulus; Elastin; Female; Glycosaminoglycans; Humans; Male; Middle Aged; Stress, Mechanical; Tensile Strength

Mesenchymal stem cells (MSCs) are known to be capable of suppressing inflammatory responses. We previously reported that intra-abdominal implantation of bone marrow-derived MSCs (BM-MSCs) sheet by laparotomy attenuated angiotensin II (AngII)-induced aortic aneurysm (AA) growth in apolipoprotein E-deficient (apoE-/-) mice through anti-inflammation effects. However, cell delivery by laparotomy is invasive; we here demonstrated the effects of multiple intravenous administrations of BM-MSCs on AngII-induced AA formation.. BM-MSCs were isolated from femurs and tibiae of male apoE-/- mice. Experimental AA was induced by AngII infusion for 28 days in apoE-/- mice. Mice received weekly intravenous administration of BM-MSCs (n=12) or saline (n=10). After 4 weeks, AA formation incidence, aortic diameter, macrophage accumulation, matrix metalloproteinase (MMP)' activity, elastin content, and cytokines were evaluated.. AngII induced AA formation in 100% of the mice in the saline group and 50% in the BM-MSCs treatment group (P < 0.05). A significant decrease of aortic diameter was observed in the BM-MSCs treatment group at ascending and infrarenal levels, which was associated with decreased macrophage infiltration and suppressed activities of MMP-2 and MMP-9 in aortic tissues, as well as a preservation of elastin content of aortic tissues. In addition, interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1 significantly decreased while insulin-like growth factor-1 and tissue inhibitor of metalloproteinases-2 increased in the aortic tissues of BM-MSCs treatment group.. Multiple intravenous administrations of BM-MSCs attenuated the development of AngII-induced AA in apoE-/- mice and may become a promising alternative therapeutic strategy for AA progression.

Topics: Angiotensin II; Animals; Aorta; Aortic Aneurysm; Apolipoproteins E; Bone Marrow Cells; Cytokines; Disease Progression; Elastin; Femur; Inflammation; Injections, Intravenous; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Knockout

Abdominal aortic aneurysms (AAAs) are rupture-prone progressive dilations of the infrarenal aorta due to a loss of elastic matrix that lead to weakening of the aortic wall. Therapies to coax biomimetic regenerative repair of the elastic matrix by resident, diseased vascular cells may thus be useful to slow, arrest or regress AAA growth. Hyaluronan oligomers (HA-o) have been shown to induce elastic matrix synthesis by healthy and aneurysmal rat aortic smooth muscle cells (SMCs) in vitro but only via exogenous dosing, which potentially has side-effects and limitations to in vivo delivery towards therapy. In this paper, we describe the development of HA-o loaded poly(lactide-co-glycolide) nanoparticles (NPs) for targeted, controlled and sustained delivery of HA-o towards the elastogenic induction of aneurysmal rat aortic SMCs. These NPs were able to deliver HA-o over an extended period (>30 days) at previously determined elastogenic doses (0.2-20 μg ml(-1)). HA-o released from the NPs led to dose-dependent increases in elastic matrix synthesis, and the recruitment and activity of lysyl oxidase, the enzyme which cross-links elastin precursor molecules into mature fibers/matrix. Therefore, we were able to successfully develop a nanoparticle-based system for controlled and sustained HA-o delivery for the in vitro elastogenic induction of aneurysmal rat aortic smooth muscle cells.

Topics: Animals; Aorta; Aortic Aneurysm; Cell Death; Cell Proliferation; Cell Survival; Drug Delivery Systems; Elastin; Extracellular Matrix; Fluorescent Antibody Technique; Hyaluronic Acid; Kinetics; Lactic Acid; Matrix Metalloproteinase 2; Myocytes, Smooth Muscle; Nanoparticles; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polyvinyl Alcohol; Protein-Lysine 6-Oxidase; Rats; Regeneration; Static Electricity

Acute aortic dissection is a life-threatening disease with a high rate of mortality. At the Institute of Legal Medicine of the Hanover Medical School, 30 cases with aortic dissections were found during autopsy and examined histologically between 2006 and 2009. The grade of medial alterations in the form of cystic medial necrosis, elastin fragmentation, fibrosis and medionecrosis were estimated semi-quantitatively. In order to assess the normal aging process, samples of the aortic wall of 25 decedents without dissecting aneurysms were analyzed histologically. This study demonstrates that there are partly quantitative differences, particularly with a statistically significant increase in cystic medial necrosis (p<0.001) and elastin fragmentation (p<0.001), between aortas from dissecting aneurysms and the normal aging aorta, which may help to identify genetically predisposed relatives of patients with a dissection of the aorta.

Topics: Adult; Aged; Aged, 80 and over; Aging; Aorta; Aortic Aneurysm; Aortic Dissection; Arteriosclerosis; Case-Control Studies; Elastin; Female; Fibrosis; Forensic Pathology; Humans; Male; Middle Aged; Necrosis; Tunica Media

Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-β (TGF-β) signaling. Although TGF-β blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-β causes aneurysms remain ill-defined.. We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS.. Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor κB, a repressor of miR-29b, and a factor suppressed by TGF-β, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor κB inhibitor increased miR-29b levels, whereas TGF-β blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies.. We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.

Topics: Age Factors; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta; Aortic Aneurysm; Apoptosis; Apoptosis Regulatory Proteins; Cells, Cultured; Disease Models, Animal; Elastin; Female; Fibrillin-1; Fibrillins; Genetic Therapy; Losartan; Male; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; MicroRNAs; NF-kappa B; Oligonucleotides, Antisense; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Up-Regulation

In this study, we propose to use a thermal technique, Differential Scanning Calorimetry (DSC) to follow the evolution of elastin and collagen in safe and pathological cardiovascular tissues.. The first part of this study deals with the analysis of the elastin network and associated proteins during ageing (from children to old persons) in aortic walls. The second part is devoted to the characterization of the collagenic phase in aneurysms. In both cases, physical data are correlated with biochemical analyses.. For old persons aortas with atheromatous stades, elastin and associated proteins are found to interpenetrate to form a homogenous phase. Abdominal aortic aneurysms (AAA) are characterized by structural alterations of the aortic wall resulting from the degradation of elastic fibers and an increase of collagen/elastin ratio. Notable modifications are evidenced between collagen from control tissue and collagen from AAA, particularly concerning the thermal denaturation. Biochemical and thermal results are compatible with the increase of new collagen deposition and/or impairment of the collagen phase stability in the extracellular matrix of AAAs.

Topics: Adult; Aged; Aged, 80 and over; Aorta; Aortic Aneurysm; Aortic Diseases; Calorimetry, Differential Scanning; Cohort Studies; Collagen; Elastin; Female; Health; Humans; Infant; Male; Plaque, Atherosclerotic; Protein Transport; Young Adult

Regenerating elastic matrices lost to disease (e.g. in aneurysms) is vital to re-establishing vascular homeostasis but is challenged by the poor elastogenicity of post-neonatal cells. We previously showed that exogenous hyaluronan oligomers (HA-o) and TGFβ1 synergistically enhance tropo- and matrix elastin deposition by healthy adult rat aortic SMCs (RASMCs). Towards treating aortic aneurysms (AAs), which exhibit cause- and site-specific heterogeneity in matrix content/structure and contain proteolytically-injured SMCs, we investigated the impact of pre-existing elastic matrix degeneration on elastogenic induction of injured RASMCs. Elastin-rich RASMC layers at 21 days of culture were treated with 0.15 U/ml (PPE15) and 0.75 U/ml (PPE75) porcine pancreatic elastase to degrade the elastic matrix variably, or left uninjured (control). One set of cultures was harvested at 21 days, before and after injury, to quantify viable cell count, matrix elastin loss. Other injured cell layers were cultured to 42 days with or without factors (0.2 µg/ml HA oligomers, 1 ng/ml TGFβ1). We showed that: (a) the ability of cultures to self-repair and regenerate elastic matrices following proteolysis is limited when elastolysis is severe; (b) HA oligomers and TGFβ1 elastogenically stimulate RASMCs in mildly-injured (i.e. PPE15) cultures to restore both elastic matrix amounts and elastic fibre deposition to levels in healthy cultures; and (c) in severely injured (i.e. PPE75) cultures, the factors stimulate matrix elastin synthesis and crosslinking, although not to control levels. The outcomes underscore the need to enhance elastogenic factor doses based on the severity of elastin loss. This study will help in customizing therapies for elastin regeneration within AAs, based on cause and location.

Topics: Animals; Aorta; Aortic Aneurysm; Cells, Cultured; Elasticity; Elastin; Extracellular Matrix; Hyaluronic Acid; Myocytes, Smooth Muscle; Pancreatic Elastase; Rats; Rats, Sprague-Dawley; Regeneration; Swine; Tissue Engineering; Transforming Growth Factor beta1

Pathologic studies have demonstrated that aortic dissection is initiated by an intimal tear, followed by the rapid growth of an intramural hematoma that dissects the media and is characterized by elastin degradation. Genetic extracellular matrix abnormalities and proteinases may be the predisposing factors in aortic dissection, but little is known about the role of elastic fiber assembly. Fibulin-1 is an extracellular protein that is expressed in the vascular basement membrane. It regulates elastic fiber assembly and hence provides integrity in aortic structure. This study investigates the expression profiles of genes responsible for the elastolysis in the dissected human aorta, especially those coding fibulin-1, matrix metalloproteinase-9 (MMP-9), and elastin.. Intraoperative aortic samples were obtained from Chinese patients with Stanford Type A aortic dissection. Both the ascending dissected aortas (primary tear) and the adjacent intact aortas were collected for comparison. Control aortic tissues were obtained from healthy organ donors. The gene profile study was determined by the Affymetrix HG-U133A GeneChip (Affymetrix, Santa Clara, Calif) and analyzed by GeneSpring GX11.0 (Agilent Technologies Inc, Palo Alto, Calif). Only the genes displaying a net signal intensity two-fold higher than the mean background were used for analysis. To evaluate elastin expression, aortic sections were stained with Movat pentachrome stain. Fibulin-1, MMP-9, and elastin mRNA and protein expression were further confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting, respectively.. Eight male Chinese aortic dissection patients (mean age, 45.8 years) and eight gender- and age-matched organ donors were recruited for the study. On the Affymetrix platform, 2,250 of 22,283 genes (10.1%) were detectable. The dissected and adjacent macroscopically intact aorta displayed similar gene expression patterns. In contrast, 11.2% (252) of the detectable genes were differentially expressed in the dissected and control aortas. Of these, 102 genes were upregulated, and 150 genes were downregulated. Based on the gene ontology, genes that code for extracellular matrix protein components and regulating elastic fiber assembly, like fibulin-1 and elastin, were downregulated, while enzymes like MMP-9 and MMP-11 that degrade matrix proteins were upregulated in dissected aortas. RT-PCR and Western blot results further validated the results.. Our gender- and age-matched study demonstrated that the alternated genes in the elastin assembly of dissected aortas may predispose structural failure in the aorta leading to dissection. However, no significant gene alterations in the adjacent intact and dissected aortas of the same patient can be found. Therefore, the genetic changes found in the dissected aortas most likely developed before the dissection starts. The inhibition of the aberrant expression of the fibulin-1 gene and that of the related matrix proteinase may open a new avenue for preventing aortic dissection.

Topics: Adult; Aortic Aneurysm; Aortic Dissection; Blotting, Western; Calcium-Binding Proteins; Case-Control Studies; Elastin; Gene Expression Profiling; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Oligonucleotide Array Sequence Analysis; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Staining and Labeling

Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2(+/-) mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2(+/-) SMCs demonstrated increased phosphorylation of mammalian target of rapamycin (mTOR), S6 and p70S6K and increased proliferation rates compared with wild-type (WT) SMCs. Tsc2(+/-) SMCs also had reduced expression of SMC contractile proteins compared with WT SMCs. An inhibitor of mTOR signaling, rapamycin, decreased SMC proliferation and increased contractile protein expression in the Tsc2(+/-) SMCs to levels similar to WT SMCs. Exposure to alpha-elastin fragments also decreased proliferation of Tsc2(+/-) SMCs and increased levels of p27(kip1), but failed to increase expression of contractile proteins. In response to artery injury using a carotid artery ligation model, Tsc2(+/-) mice significantly increased neointima formation compared with the control mice, and the neointima formation was inhibited by treatment with rapamycin. These results demonstrate that Tsc2 haploinsufficiency in SMCs increases proliferation and decreases contractile protein expression and suggest that the increased proliferative potential of the mutant cells may be suppressed in vivo by interaction with elastin. These findings provide insights into the molecular pathogenesis of aortic disease in TSC patients and identify a potential therapeutic target for treatment of this complication of the disease.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm; Cell Proliferation; Child; Contractile Proteins; Elastin; Humans; Magnetic Resonance Angiography; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Mutation; Myocytes, Smooth Muscle; Peptides; Phenotype; Proteins; Radiography; rho GTP-Binding Proteins; Signal Transduction; Thoracic Diseases; TOR Serine-Threonine Kinases; Transcription Factors; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Tunica Intima

To determine the role of multinucleated giant cells (MGCs) in cardiovascular diseases.. MGCs are a hallmark of giant cell arteritis. They are also described in atherosclerotic plaques from aortic aneurysms and carotid and coronary arteries. Herein, we demonstrate that the cholate-containing Paigen diet yields many MGCs in atherosclerotic plaques of apolipoprotein E-/- mice. These mice revealed a 4-fold increase in MGC numbers when compared with mice on a Western or Paigen diet without cholate. Most of the MGCs stained intensively for cathepsin K and were located at fibrous caps and close to damaged elastic laminae, with associated medial smooth muscle cell depletion. During in vitro experiments, MGCs demonstrated a 6-fold increase in elastolytic activity when compared with macrophages and facilitated transmigration of smooth muscle cells through a collagen-elastin matrix. An elastin-derived hexapeptide (Val-Gly-Val-Ala-Pro-Gly [VGVAPG]) significantly increased the rate of macrophage fusion, providing a possible mechanism of in vivo MGC formation. Comparable to the mouse model, human specimens from carotid arteries and aortic aneurysms contained cathepsin K-positive MGCs.. Apolipoprotein E-/- mice fed a Paigen diet provide a model to analyze the tissue-destructive role of MGCs in vascular diseases.

Topics: Animals; Antigens, Differentiation; Aortic Aneurysm; Apolipoproteins E; Atherosclerosis; Carotid Artery Diseases; Cathepsin K; Cell Fusion; Cell Movement; Cells, Cultured; Cholates; Collagen; Dietary Fats; Disease Models, Animal; Elastin; Endotoxins; Giant Cells, Foreign-Body; Humans; Immunohistochemistry; Interleukin-4; Macrophages, Peritoneal; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oligopeptides; Time Factors; Toll-Like Receptor 4

The pathogenesis of aortic aneurysm (AA) is characterized by degradation of extracellular matrix with increased matrix metalloproteinases (MMPs) and inflammatory reaction. Doxycycline (DOXY) has been reported to control the extension of AA by regulation of MMP. However, systemic administration may cause adverse side effects. In this study, we demonstrated the possibility of local administration of DOXY controlled-release biodegradable fiber (DCRBF) for AA in mice. DCRBF was fabricated by biodegradable polymer (polylactic acid; PLA) mixed with DOXY using an electrospinning technique. DCRBF was cocultured with SMCs, macrophages and aortic tissue, and placed on an abdominal aortic aneurysm which induced apolipoprotein E-deficient mice. We evaluated gene and protein expression of proteases, elastin and inflammatory markers. In the presence of DCRBF, MMP-12 was significantly decreased, TGF-β1 and Lox were significantly increased in SMC gene expression, MMP-9 and -12 significantly decreased gene expression of macrophages. The DCRBF preserved elastin content and decreased MMP-2 and -9 in aortic tissue. In addition, IGF-1 and TIMP-1 were significantly increased and IL-6 and TNF-α were significantly decreased with DCRBF in vivo. In conclusion, our results suggested that local administration of DCRBF may become a promising alternative therapeutic strategy for AA.

Topics: Animals; Aorta; Aortic Aneurysm; Biocompatible Materials; Chemokines; Coculture Techniques; Delayed-Action Preparations; Disease Models, Animal; Doxycycline; Elasticity; Elastin; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins; Lactic Acid; Macrophages; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Myocytes, Smooth Muscle; Polyesters; Polymers; Tissue Culture Techniques; Tissue Inhibitor of Metalloproteinases

Ascending aortic aneurysms (AA) are a common, though poorly understood medical condition.. To document the histological changes in a large series of human ascending AA, and to correlate these changes with clinical variables.. 111 ascending AA were excised at surgery over a 3 year period. Each aneurysm was received as a continuous ring of tissue. Sections were taken from the anterior, posterior, greater and lesser curvature of the aorta and graded in a semi-quantitative fashion for the degree of elastin fragmentation, elastin loss, smooth muscle cell (SMC) loss, intimal changes and inflammation.. Mean patient age at surgery was 58.7 (15.6) years; there were 70 men and 41 women. 12 patients had Marfan syndrome, 34 (30.6%) had a bicuspid aortic valve (BAV), while 71 (64.0%) had a tricuspid aortic valve (TAV). Inflammatory cells were present in 28 cases (25.2%) and were confined to the adventitia. No particular region of the aortic circumference was more severely affected, however a BAV was associated with significantly less intimal change, and less fragmentation and loss of elastic tissue compared with patients with a TAV. Advanced age (>65 years), female gender and Marfan syndrome were all associated with more severe elastin degeneration and smooth muscle cell loss (p<0.05 for all).. Results indicate a wide variation in the histological appearance in ascending AA, depending on patient characteristics. They suggest that the underlying aneurysm pathogenesis may also be highly variable; this warrants further investigation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aortic Aneurysm; Aortic Valve; Elastic Tissue; Elastin; Female; Humans; Male; Marfan Syndrome; Middle Aged; Muscle, Smooth, Vascular; Sex Factors; Tunica Intima

Aortic aneurisms are frequently asymptomatic but can induce dramatic complications. The diagnosis is only based on the aortic diameter and not on a structural and compositional basis. In this preliminary study, we propose infrared microspectroscopy to nondestructively probe normal and aneurismal human aortas. Spectra from 19 human ascending aortic biopsies (10 normal and 9 aneurismal) were acquired using infrared microspectroscopy. A 1500 x 150 microm(2) area of each 7-microm thick cryosection was investigated using a 30-microm spatial resolution with a total of about 200 spectra per sample. Spectral differences between normal and aneurismal tissues were mainly located in spectral regions related to proteins, such as elastin and collagen, and proteoglycans (1750-1000 cm(-1)). Tissue heterogeneity and sample classification have been evaluated using hierarchical cluster analysis of individual or mean spectra and their second derivative. Using spectral range related to proteins, 100% of good classification was obtained whereas the proteoglycan spectral range was less discriminant. This in vitro study demonstrates the potential of such technique to differentiate between normal and aneurismal aortas using selected spectral ranges. Future investigations will be focused on these specific spectral regions to determine the role of elastin and collagen in the discrimination of normal and pathological aortas.

Topics: Aorta; Aortic Aneurysm; Biopsy; Collagen; Elastin; Extracellular Matrix; Female; Humans; Male; Spectrophotometry; Spectrophotometry, Infrared; Spectroscopy, Fourier Transform Infrared

Cutis laxa is an acquired or inherited condition characterized by redundant, pendulous and inelastic skin. Autosomal dominant cutis laxa has been described as a benign disease with minor systemic involvement.. To report a family with autosomal dominant cutis laxa and a young girl with sporadic cutis laxa, both with variable expression of an aortic aneurysmal phenotype ranging from mild dilatation to severe aneurysm or aortic rupture.. Histological evaluation of aortic aneurysmal specimens indicated classical hallmarks of medial degeneration, paucity of elastic fibres, and an absence of inflammatory or atherosclerotic lesions. Electron microscopy showed extracellular elastin deposits lacking microfibrillar elements. Direct sequencing of genomic amplimers detected defects in exon 30 of the elastin gene in affected individuals, but did not in 121 normal controls. The expression of mutant elastin mRNA forms was demonstrated by reverse transcriptase polymerase chain reaction analysis of cutis laxa fibroblasts. These mRNAs coded for multiple mutant tropoelastins, including C-terminally truncated and extended forms as well as for molecules lacking the constitutive exon 30.. ELN mutations may cause severe aortic disease in patients with cutis laxa. Thus regular cardiac monitoring is necessary in this disease to avert fatal aortic rupture.

Topics: Adult; Aortic Aneurysm; Child, Preschool; Cutis Laxa; Elastin; Female; Humans; Male; Mutation

This report describes 2 cases of spontaneous aortic dissecting hematoma in young Border Collie and Border Collie crossbred dogs. Histology was performed in one of the cases involving an unusual splitting of the elastin present within the wall of the aorta, consistent with elastin dysplasia as described in Marfan syndrome in humans. The first case involved a young purebred Border Collie that died suddenly and the second case involved a Border Collie crossbred dog that died after a 1-month history of seizures. Gross lesions included pericardial tamponade with dissection of the ascending aorta in the former case and thoracic cavity hemorrhage, mediastinal hematoma, and aortic dissection in the latter. Histologic lesions in the case of the Border Collie crossbred dog included a dissecting hematoma of the ascending aorta with elastin dysplasia and right axillary arterial intimal proliferation.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm; Aortic Dissection; Aortic Rupture; Dog Diseases; Dogs; Elastin; Fatal Outcome; Hematoma; Male; Seizures

We aimed to establish an enzyme-linked immunosorbent assay (ELISA) for measuring soluble elastin fragments (sELAF) in serum and to reveal its usefulness in diagnosing acute aortic dissection.. Acute aortic dissection is a life-threatening disease of the aorta. However, the diagnosis is still frequently missed, especially at onset. The establishment and clinical availability of simplified laboratory test(s) to help diagnose and screen acute aortic dissection patients is therefore urgently needed.. An ELISA to measure sELAF in serum was developed using the newly created double monoclonal antibodies which recognize the different epitopes of human aortic elastin. Twenty-five acute aortic dissection patients, 50 patients with acute myocardial infarction, and 474 healthy individuals were enrolled in the study. The sELAF levels from healthy subjects gradually increased with aging. When the cutoff point for positivity was set at the mean + 3SD above the mean of those in healthy subjects at each age, 16 acute aortic dissection patients (64.0%) were found to be positive, while only one acute myocardial infarction patient was positive (2.0%). Acute aortic dissection patients with either an open or a partially open pseudolumen were found to be 88.9% positive for sELAF, while those with its early closure was 0% positive. The difference in the sELAF levels between acute aortic dissection patients with and without a thrombotic closure of false lumen was significant (60.3 +/- 15.6 vs 135.4 +/- 53.2 ng/ml, p < 0.005).. The sELAF level in serum may be a useful marker for helping both diagnose and screen acute aortic dissection, while also helping distinguish acute aortic dissection from acute myocardial infarction.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Aortic Aneurysm; Aortic Dissection; Biomarkers; Elastin; Enzyme-Linked Immunosorbent Assay; Humans; Middle Aged; Solubility

Topics: Acute Disease; Aortic Aneurysm; Aortic Dissection; Aortography; Biomarkers; Echocardiography, Transesophageal; Elastin; Humans; Magnetic Resonance Imaging; Sensitivity and Specificity; Tomography, X-Ray Computed

To estimate elastin metabolism in aneurysm, urinary levels of desmosine and elastin peptide in patients (n=23, range 54 to 85 years old) with aneurysm were measured by ELISA and compared between two control groups divided by age (<10 years old and >20 years old). The amounts of urinary desmosine and elastin peptide in the aneurysm group were significantly increased compared with those in the older control group (>20 years old). There was a correlation between urinary desmosine and elastin peptide in the young group. On the other hand, no such correlation was observed in the aneurysm group and the older control group. The distribution of the ratio (desmosine/elastin peptide) in the aneurysm group was different from that of the young control group. We conclude that assay of elastin peptide and desmosine in urine are useful in characterizing elastin degradation in a patient with aneurysm.

Topics: Adult; Aged; Aged, 80 and over; Aortic Aneurysm; Child; Child, Preschool; Desmosine; Elastin; Humans; Infant; Middle Aged; Peptide Fragments

Arterial aneurysms exhibit a loss of elastin and an increase in the plasminogen activators urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA). Because u-PA, t-PA, and plasmin have a limited proteolytic activity against elastin, the role of plasminogen activators in the aneurysmal disease is unclear. To investigate this question, we overexpressed plasminogen activator inhibitor-1 (PAI-1), an inhibitor of t-PA and u-PA, in a rat model of aortic aneurysm.. Guinea pig-to-rat aortic xenografts were seeded with syngeneic Fischer 344 rat smooth muscle cells retrovirally transduced with the rat PAI-1 gene (LPSN group) or the vector alone (LXSN group). Some grafts were not seeded with cells (NO group). Western blots showed increased PAI-1 in grafts from the LPSN group compared with LXSN and NO groups. All grafts in the NO group (n=8) and 40% in the LXSN group ruptured between days 4 and 14. At 4 weeks in the LXSN group, the remaining unruptured grafts (n=6) were aneurysmal (diameter increase > or =100%), whereas in the LPSN group (n=6) none of the grafts had ruptured or were aneurysmal. Elastin was preserved in the LPSN group. t-PA, the major PA expressed in the model, was decreased in the LPSN group compared with the other groups, as determined by zymography. Quantitative zymography showed decreased levels of two matrix metalloproteinases (MMPs), a 28-kD caseinase, and activated MMP-9 in the LPSN group.. The blockade of plasminogen activators prevents formation of aneurysms and arterial rupture by inhibiting MMP activation.

Topics: Animals; Aorta; Aortic Aneurysm; Aortic Rupture; Desmosine; Elastin; Guinea Pigs; Immunization; Male; Metalloendopeptidases; Plasminogen Activator Inhibitor 1; Plasminogen Activators; Rats; Rats, Inbred F344; Time Factors; Tissue Plasminogen Activator; Transplantation, Heterologous

In order to clarify the degradation of elastin under abnormal conditions, we examined the aortic elastolytic activity in rat experimental diabetes mellitus induced by treatment with streptozotocin and in rat experimental aneurysm induced by treatment with an inhibitor of lysyloxidase (beta-aminopropionitrile: BAPN). Measurement of the aortic elastolytic activity used 14C-labeled elastin as the substrate, and the determined value was compared with the aortic lysosomal enzyme (acid phosphatase) activity. In the case of experimental diabetes, the aortic elastolytic activity was not changed, but the aortic acid phosphatase activity was significantly increased compared with the control. In the case of the experimental aneurysm, the aortic elastolytic activity measured after 2 and 3 weeks was increased compared with each control. There was a negative correlation (r=-0.435, n=36) between the elastolytic activity and the cross-linking (desmosine) content in the aorta. The ratio of elastolytic activity to desmosine content was significantly increased compared with the control. Therefore, the degradation of aortic elastin in the experimental aneurysm was caused by elastase, not by lysosomal enzymes. We concluded that an elastase-like enzyme mainly contributed to the degradation of elastin in the experimental aneurysm since the inhibitory pattern of the elastolytic activity in the experimental aneurysm was similar to that of pancreatic elastase.

Topics: Animals; Aorta; Aortic Aneurysm; Carbon Radioisotopes; Diabetes Mellitus, Experimental; Elastin; Isoflurophate; Male; Oligopeptides; Pancreas; Pancreatic Elastase; Rats; Rats, Wistar

Abdominal aortic aneurysms are characterised by changes in the extracellular matrix of the arterial media, in particular a reduction in elastin concentration. These changes are mediated by increased levels of endogenous matrix metalloproteinases (MMPs). Recently, calcium channel blockers have been shown to increase the proteolytic activity of MMP-2 secreted by vascular smooth muscle cells. It may therefore by hypothesised that calcium antagonists may potentiate the activity of MMPs in aneurysmal disease and thus accelerate AAA expansion. In this study, the ability of amlodipine--a calcium antagonist--to influence elastin degradation, was assessed in a previously described model of aneurysmal disease.. Porcine aortic segments (n = 8) were pre-incubated in exogenous pancreatic elastase for 24 h prior to culture in standard conditions for 6 days with 10 and 100 micrograms/l amlodipine. Control segments were cultured both with and without amlodipine and without elastase. At the termination of culture MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereological analysis of EVG stained sections.. Gel enzymography demonstrated significantly increased MMP-9 activity in the amlodipine treated segments, median 4.218 vs. 2.809 arbitrary units (p < 0.01) and this elevated activity was reflected in a significant destruction of medial elastin 27.0 vs. 40.5% (p < 0.05).. Therapeutic ranges of amlodipine significantly enhanced elastin degradation and potentiated MMP-9 activity within the aortic organ cultures.

Topics: Amlodipine; Animals; Aorta; Aortic Aneurysm; Calcium Channel Blockers; Collagenases; Disease Models, Animal; Elastin; In Vitro Techniques; Matrix Metalloproteinase 9; Swine

Nitrite ion is a by-product of nitrogen oxides (nitric oxide and nitrogen dioxide) from cigarette smoke and is used as a preservative for curing meats. Therefore, study of the reaction of nitrite with elastin in vitro was undertaken. By colorimetric assay, reactivity of nitrite with insoluble elastin at neutral pH, 37 degrees C, and physiologic concentration was confirmed. In histochemical studies on in situ human aortic elastin, nitrite-treated sections displayed marked structural disruptions. Determinations of fluorescence and absorbance on nitrite-treated soluble bovine elastin revealed marked alterations of fluorescence, and increased UV and visible absorbance. Amino acid analysis confirmed that it reacted with tyrosine. The findings indicate that non-enzymatic nitration by nitrite may have deleterious effects on elastin in vivo and may provide insights into the pathogenesis of chronic elastin degenerative processes, including aortic aneurysms, pulmonary emphysema, and premature skin wrinkling, all of which have been well known to have associations with cigarette smoking.

Topics: Amino Acids; Animals; Aorta; Aortic Aneurysm; Cattle; Dose-Response Relationship, Drug; Elastin; Histocytochemistry; Humans; Nitrites; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet

Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, induction of endogenous metalloproteinases (MMPs), and development of a chronic inflammatory infiltrate. Despite intensive analysis of end-stage tissue, aneurysm pathogenesis remains obscure. The aim of this study was to develop an in vitro model of aneurysmal disease.. Porcine aortic organ cultures were preincubated with pancreatic elastase before culture in standard conditions for up to 14 days. The extent of matrix degradation at various time points was determined by quantitative histologic estimation of collagen and elastin concentration. Endogenous metalloproteinase production within the tissue was quantified by gel enzymography and immunoblotting. A separate series of experiments was performed to investigate the effect of incorporating autologous leukocytes into the culture system.. Although exogenous elastase was removed after 24 hours, substantial degradation of the aortic extracellular matrix occurred in the subsequent 13 days in tissue culture. Analysis of samples preincubated with elastase (100 U/ml) for 24 hours before tissue culture demonstrated that elastin degradation occurred in a time-dependent manner (p < 0.001) and was not confined to the initial phase of exogenous elastase activity. Gelatin gel enzymography revealed a time-related production of metalloproteinases (55 to 250 kDa) within the aortic tissue. The presence of MMPs-1, 2, 3, and 9 was determined by immunoblotting. Immunohistochemistry identified the vascular smooth-muscle cell as the source of MMPs-1, 2, and 3. Addition of autogenous leukocytes to elastase-pretreated tissue initiated an inflammatory infiltrate within the aortic wall, which further enhanced both matrix degradation and MMP production (p < 0.001).. These data demonstrate that aortic samples pretreated with elastase before tissue culture undergo matrix degradation with MMP production and the development of an inflammatory infiltrate. These changes mirror the pathophysiological events within established aneurysms. It is suggested that this model may be useful in understanding early pathogenic events within aneurysmal tissue.

Topics: Animals; Aortic Aneurysm; Collagen; Elastin; Extracellular Matrix; Immunoblotting; Leukocytes; Metalloendopeptidases; Muscle, Smooth, Vascular; Organ Culture Techniques; Pancreatic Elastase; Swine

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm; Chemotaxis, Leukocyte; Collagenases; Elastin; Enzyme Induction; Extracellular Matrix; Gelatinases; Leukocytes; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Metalloendopeptidases; Organ Culture Techniques; Pancreatic Elastase; Stress, Mechanical; Swine

While localization of atherosclerosis and aneurysms to the infrarenal aorta has been attributed, in part, to hemodynamic factors, anatomic differences between the proximal and the distal aorta may also be important. Our purpose was to determine the changes in content and organization of major structural proteins (elastin and collagen) throughout the normal human aorta.. Biochemical analysis for desmosine-isodesmosine (elastin) and hydroxyproline (collagen) content was done by HPLC on complete 1-cm transverse rings removed from the ascending and descending thoracic aorta and abdominal supraceliac, suprarenal, and midinfrarenal aorta. Elastin and collagen content was normalized to lumenal surface area and compared by ANOVA: Light microscopy and optical micrometry were used to determine changes in intimal, medial, and adventitial thickness and number of elastin lamellae at each level.. Both collagen/cm2 and elastin/cm2 decrease from the proximal to distal aorta. Collagen content did not differ among the three abdominal segments, but there was a 58% decrease in elastin between the suprarenal and the infrarenal aorta. The proportion of elastin and collagen does not differ throughout the aorta except in the infrarenal aorta where there is decreased elastin relative to collagen.. Collagen and elastin in the distal aorta bear an increased load as compared to the proximal aorta. The infrarenal aorta differs biochemically and histologically from the remainder of the aorta. A decrease in infrarenal elastin without a corresponding decrease in collagen may effect the compliance and integrity of the distal aorta. These anatomic differences may be important in predisposing the infrarenal aorta to atherosclerosis and aneurysm formation.

Topics: Adult; Aorta; Aortic Aneurysm; Aortic Diseases; Arteriosclerosis; Collagen; Elastin; Female; Humans; Male

Aneurysmal dilation of the aorta with subsequent rupture or dissection occurs frequently in patients with Marfan syndrome and is the primary cause of morbidity. These complications are related to the altered composition and disorganized structure of the aortic media. Our goal was to use high-frequency ultrasonic tissue characterization to identify these structural changes in abnormal aorta from patients with Marfan syndrome. We measured integrated backscatter and anisotropy of backscatter of ultrasound from specimens of aorta from patients with Marfan syndrome undergoing aortic root replacement and compared these values with those from aortic specimens of patients without clinical aortic pathology.. Aortic tissue was obtained at the time of surgery from 11 patients with Marfan syndrome undergoing repair of an aortic aneurysm or dissection. Normal tissue was obtained at the time of autopsy from 8 patients without evidence of aortic disease. Acoustic microscopy at 50 MHz was performed to measure integrated backscatter from each specimen. The magnitude of ultrasonic anisotropy of backscatter for each tissue type was determined as an index of the three-dimensional (3D) organization of the vessel matrix. The collagen content of each specimen was determined with a hydroxyproline assay. Marfan aortas exhibited less backscatter than did normal aortas (-40.9 +/- 2.9 versus -32.6 +/- 2.2 dB for patients with Marfan syndrome and healthy subjects, respectively, P < .0001). No significant difference in collagen concentrations was observed between normal and Marfan aorta (262.7 +/- 52.7 versus 282.4 +/- 41.8 mg/g tissue for normal and Marfan aortas, respectively, P = .42), despite the large difference in backscatter. Histological analysis revealed striking differences in both the amount and organization of the elastin in the aortic aneurysm segments from patients with Marfan syndrome compared with normal aorta. Normal aorta was characterized by well-formed elastin fibers arranged in a lamellar pattern. The media from aneurysms in Marfan aorta exhibited a profound decrease in elastin content that was associated with loss of the highly aligned and ordered lamellar arrangement. The directional dependence of scattering, or ultrasonic anisotropy, also differed dramatically between the two tissue types. Backscatter from normal aorta decreased substantially when the media was insonified parallel compared with perpendicular to the principal axis of the elastin fibers. Marfan aorta exhibited a much smaller directional dependence of scattering. Normal aortas manifested a 14-fold greater ultrasonic anisotropy than did Marfan aortas (24.1 +/- 3.7 versus 12.4 +/- 3.3 dB for normal and Marfan aortas, P < .0001), which is indicative of the profound extent of matrix disorganization in Marfan syndrome.. These data show that high-frequency ultrasonic tissue characterization sensitively detects changes in vessel wall composition and organization that occur in the aorta of patients with Marfan syndrome. Aortic segments from these patients manifested a significant decrease in integrated backscatter compared with normal aorta (approximately 8 dB, or greater than a 6-fold decrease in scattering). A 15-fold reduction in the ultrasonic anisotropy of Marfan tissue was observed, which suggests a marked disorganization of the 3D architecture of these aortas. These data support the hypothesis that high-frequency ultrasonic tissue characterization may be useful for identifying abnormalities of vessel wall composition, architecture, and material properties.

Topics: Adult; Anisotropy; Aorta; Aortic Aneurysm; Aortic Dissection; Collagen; Elastin; Female; Humans; Male; Marfan Syndrome; Tunica Media; Ultrasonography

Topics: Aorta; Aortic Aneurysm; Aortic Dissection; Collagen; Elastin; Extracellular Matrix Proteins; Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Ultrasonography

Topics: Adrenergic beta-Antagonists; Aortic Aneurysm; Aortic Dissection; Aortic Valve Insufficiency; Elastin; Fibrillins; Genetic Counseling; Humans; Marfan Syndrome; Microfilament Proteins; Mitral Valve Insufficiency; Myofibrils; Patient Care Team; Phenotype

Although elastin depletion is thought to be an etiologic factor in abdominal aortic aneurysm, little is known about its transcription and posttranslational modification in normal and diseased human aorta. Our objectives were to quantify total elastin and elastin cross-links (desmosine/isodesmosine [DID]) and to determine if elastin mRNA was detectable in the disease-prone infrarenal aorta from patients with abdominal aortic aneurysm and a comparative group with no aneurysmal diseases. After preliminary extraction and thermolysin digestion, content of DID and the elastin tetrapeptide, valine-alanine-proline-glycine (VAPG), were determined by high-performance liquid chromatography. Tissue mRNA was studied by Northern blot analysis. Mean values (+/- SE) were compared by Student's t test. The proportion of insoluble elastin was markedly decreased in abdominal aortic aneurysm tissue (1.3% +/- 0.04% vs 12% +/- -2.8%; p less than 0.001). There was no difference in the small percentage of elastin solubilized during extraction in abdominal aortic aneurysm (5.3% +/- 1%) and no aneurysmal disease (6.0% +/- 1.2%; p = 0.71) tissues. The DID concentration of insoluble elastin was not different for abdominal aortic aneurysm and no aneurysmal disease tissue (0.18% +/- 0.07 vs 0.18 +/- 0.05 nm DID/nm VAPG; p = 0.97). On the basis of VAPG content, only 26% +/- 4% of the sodium hydroxide insoluble residue from abdominal aortic aneurysm was elastin; the predominate protein(s) was high in polar amino acids. Elastin mRNA was detectable in all tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Amino Acid Sequence; Aorta, Abdominal; Aortic Aneurysm; Blotting, Northern; Chromatography, High Pressure Liquid; Desmosine; Elastin; Humans; Isodesmosine; Linear Models; Molecular Sequence Data; RNA, Messenger; Thermolysin

Weanling Sprague-Dawley rats received beta-aminopropionitrile (BAPN) and/or hypertensive treatment, namely, heminephrectomy and administration of deoxycorticosterone acetate-NaCl. The BAPN-treated rats (lathyritic rats) died of dissecting aneurysm, and the victims with hypertensive treatment was greater in number and died earlier than those without the treatment, indicating that the rise of blood pressure promoted the onset of dissecting aneurysm. The elastic architecture of the ascending aortic media was examined not only by transmission electron microscopy with tannic acid stain and/or toluidine blue O stain, but also by scanning electron microscopy after hot formic acid treatment, and the area of interlaminar elastic fibers were morphometrically analyzed by a point counting method using transmission electron microscopic photographs. In the lathyritic rats, interlaminar elastic fibers showed a significant reduction compared with the control rats, and elastic fibers tended to become round-shaped and were frequently spotted with glycosaminoglycan, which suggest a disturbance of elastogenesis. On the other hand, elastic laminae were not disrupted and smooth muscle cells were well preserved. These results suggest that the alteration of the elastic architecture causes an unstable connection between each elastic lamina, and is related to the initiation and the progression of dissecting aneurysm.

Topics: Aminopropionitrile; Animals; Aorta; Aortic Aneurysm; Aortic Dissection; Blood Pressure; Body Weight; Elastic Tissue; Elastin; Glycosaminoglycans; Hypertension; Lathyrism; Male; Rats; Rats, Inbred Strains

The decreased elastin concentration found in abdominal aortic aneurysms (AAAs) may result from a differential synthetic response wherein elastin gene expression fails to increase in parallel with type I procollagen (COL I) gene expression. The purpose of this study is to determine tissue mRNA levels for elastin and COL I in AAAs compared with levels in normal, age-matched aorta and to determine the relationship between aging and COL I gene expression.. Total RNA exacted from normal infrarenal aortic tissue (n = 7) and AAA (n = 10) tissue was subjected to Northern analysis. Mean values for COL I, elastin, and alpha-tubulin mRNA levels were compared by use of the Student t test. Age and COL I mRNA levels were analyzed by regression analysis.. COL I mRNA was increased significantly in AAAs (1.18 +/- 0.13) compared with normal aortas (0.14 +/- 0.05). A commensurate increase in elastin mRNA (AAAs, 0.11 +/- 0.02, vs normal aortas, 0.39 +/- 0.2) was absent. There was no correlation between age and COL gene expression.. The decreased elastin concentration relative to collagen in AAAs may be explained, in part, by the changes in message level of elastin and collagen. The enhanced COL I gene expression in AAAs is unrelated to age.

Topics: Aging; Aorta, Abdominal; Aortic Aneurysm; Aortic Diseases; Arterial Occlusive Diseases; Autoradiography; Blotting, Northern; Elastin; Gene Expression; Humans; Middle Aged; Procollagen; RNA, Messenger

The biochemical mechanisms by which hypertension accelerates atherosclerosis and increases the risk of aortic aneurysm rupture are poorly understood. This study evaluates the effects of hypertension on aortic trace element concentrations and antioxidant status in tissue removed from 26 normotensive (NT) and 20 hypertensive (HT) patients. Twenty-seven of 46 patients (59%) had aneurysmal (AA), and 19 of 46 (41%) had occlusive disease (OD). Aortic iron concentrations were markedly higher in both OD and AA tissue compared with controls. A similar trend was observed with copper concentrations, with the highest elevations observed in HT AA tissues. No significant differences were observed in zinc concentrations, except that HT AA aorta had significantly lower zinc levels than either OD or control tissue. Aortic ascorbic acid concentrations in diseased aorta were lower than those of controls, but independent of blood pressure. Copper-zinc-superoxide dismutase activity was similarly reduced, with the lowest activity observed in diseased aorta from HT patients. Only HT AA aorta had significantly higher manganese-superoxide dismutase activity than controls. The aortas of patients with AA had significantly lower amounts of elastin and greater elastase activity than either controls or those with OD. However, the differences were independent of blood pressure. Hypertensive patients with OD and AA had 31% more and 27% less aortic collagen, respectively, than their NT counterparts (P less than 0.05). These data suggest that the reduction in aortic collagen and elastin in HT patients with AA compared with their NT counterparts may explain the larger size of aneurysms and predispose to their eventual rupture. Furthermore, the diminished antioxidant status associated with HT predisposes to lipid peroxidation, which contributes to the acceleration of these processes. Our studies were conducted in patients with established aortic aneurysmal and occlusive disease. Whether these observations are pertinent to the pathogenesis of AA and OD remains unclear and merits further study.

Topics: Antioxidants; Aorta; Aortic Aneurysm; Arteriosclerosis; Ascorbic Acid; Blood Pressure; Collagen; Copper; Elastin; Humans; Hypertension; Iron; Lipid Peroxidation; Male; Superoxide Dismutase; Trace Elements; Zinc

The predominant pathologic feature of abdominal aortic aneurysm is elastin destruction, and elastin destruction may be mediated by inflammation. In this investigation serial sections of abdominal aortic aneurysm specimens were selectively stained to study the relationship between inflammation and elastin degradation. In addition, soluble aortic extracts were examined for the presence of immunoglobulins. An inflammatory infiltrate was present in 8 of 10 of the abdominal aortic aneurysm specimens examined. The infiltrate was mononuclear, commonly located at the junction of the media and adventitia; it did not codistribute with loss of elastin. The presence of an inflammatory component in abdominal aortic aneurysm was associated with a large amount of immunoglobulin in soluble extracts from aneurysmal tissue compared to atherosclerotic and normal control extracts. This study further characterizes the microscopic pathology of abdominal aortic aneurysm and describes the presence of immunoglobulin in soluble tissue extracts. In addition, the possible role of inflammation in abdominal aortic aneurysm as it relates to protease expression is detailed.

Topics: Aorta, Abdominal; Aortic Aneurysm; Aortitis; Elastin; Humans; Immunoglobulins

Elastin of the ascending aortic media of 10 cases with type A dissecting aneurysm, 14 hypertensive cases, and 30 control cases were prepared by the treatment of aortas with hot formic acid, and three-dimensional architecture was observed by scanning electron microscopy. In the control cases, elastin showed framework-like continuous structure consisting of elastic laminae, and interlaminar fibers that interconnected the laminae. In 6 of 10 cases of dissecting aneurysm, the interlaminar fibers were apparently irregular in arrangement and shape, and decreased in number, especially in the outer media. This architectural alteration resulted in a rarefaction of interconnection between the elastic laminae in the media, and possibly resulted in the local weakness against the dissecting force of the laminae. This medial weakness may be related to the mechanism of initiation and progression of dissecting aneurysm. The cystic medial necrosis (CMN) was found in 3 cases, but only 1 of them was accompanied by a mild decrease of the interlaminar fibers in the area outside of CMN, suggesting that the initiation of CMN did not directly relate to the decrease of the interlaminar fibers. The aortic media of hypertensives generally showed an increase of interlaminar fibers, but their focal decrease was encountered in the outer media of 3 cases. These findings suggest that the decrease of the interlaminar fibers of medial elastin seen in dissecting aneurysms were related to hypertension.

Topics: Adult; Aged; Aged, 80 and over; Aorta; Aortic Aneurysm; Aortic Dissection; Elastin; Female; Humans; Hypertension; Male; Marfan Syndrome; Microscopy, Electron, Scanning; Middle Aged

We studied the histologic and histometric features of the aortic media in cases of dissecting aneurysm in order to clarify the pathologic background of this condition. The results were then compared with cases of true aneurysm and control specimens of "normal" aging aorta. Most cases of dissecting aneurysm and true aneurysm, as well as a number of control specimens, showed severe cystic medial necrosis, and therefore this feature does not appear to be specific to dissecting aneurysm. Fibrosis was noted in the process of repair of medionecrosis in dissecting aneurysm, true aneurysm, and controls. The main pathologic features of the aortic media in dissecting aneurysm included a higher grade of elastin fragmentation (offensive factor) and less fibrosis (defensive factor). Our findings indicate that the pathologic balance between these offensive and defensive factors is an important consideration when evaluating the pathogenesis of dissecting aneurysm.

Topics: Aged; Aging; Aortic Aneurysm; Aortic Dissection; Elastin; Female; Fibrosis; Humans; Male; Necrosis; Reference Values; Retrospective Studies

Aneurysms of the abdominal aorta occur with atherosclerosis or connective tissue disorders. Changes of three components of aortic media, smooth muscle cells, elastin, and collagen, which could contribute to medial weakening, are discussed. Smooth muscle cells cultured from the aging abdominal aorta (normal, atherosclerotic, or aneurysmal) have limited replicative potential at five to six cell doublings, whereas cells from aneurysmal thoracic aorta undergo more than 20 cell doublings in culture. The elastin content is much reduced in aneurysms and this is associated with an increase in elastase activity of medial homogenates to 17.8 U/ng of deoxyribonucleic acid (DNA) compared with 8.3 and 4.4 U/ng of DNA in atherosclerotic and normal aorta, respectively. An elastinolytic enzyme has been purified from aneurysmal aorta and appears to have different properties from human leukocyte elastase. Ruptured aneurysms are associated with an increased total collagenase activity but the increase could be stimulated by, or result from, an influx of inflammatory cells and does not necessarily have a causal significance. In patients with a family history of aneurysm there appears to be a decreased content of type III collagen in aortic media: 24% +/- 4% compared with 32% +/- 5% in most aneurysms. Familial aneurysms are most common in women, and preliminary results suggest that a polymorphic variant of the type III collagen gene, defined by restriction enzyme digest, may be associated with aneurysmal disease in women. The genetic approach may define causal mechanisms predisposing patients to aneurysmal dilatation.

Topics: Aged; Aorta, Abdominal; Aortic Aneurysm; Collagen; DNA; Elastin; Genotype; Humans; Lipids; Microbial Collagenase; Middle Aged; Muscle, Smooth, Vascular; Pancreatic Elastase; Phenotype

Propranolol prevents or delays the formation of aortic aneurysms in both the lathyritic turkey and the Blotchy mouse models. This finding in the turkey is reported to be a direct effect on crosslinking of aortic collagen and elastin, independent of effects on pulse and blood pressure. The present work was performed to evaluate this hypothesis in the mouse model by studying the effect of propranolol on the insolubility of matrix proteins of skin, which would isolate the phenomenon from direct hemodynamic effects. Eight 6- to 8-week-old Blotchy mice were fed a diet containing 0.10% (w/w) propranolol for 12 weeks, and six Blotchy controls ate regular chow. At sacrifice the skins were extracted with 8 M urea, and the soluble and insoluble fractions were analyzed for hydroxyproline to determine the collagen contents. The elastin was estimated by subtracting the collagen from the insoluble fraction. There was a 147% increase in insoluble elastin with propranolol and a lesser increase of 54% in insoluble collagen. These results suggest that propranolol has a direct effect on crosslinking of matrix components.

Topics: Animals; Aortic Aneurysm; Collagen; Connective Tissue; Elastin; Male; Mice; Mice, Mutant Strains; Propranolol; Skin

Recent evidence indicates that metabolism of elastin may be altered in patients with different types of infrarenal aortic disease and that the phenotypic expression of aortic disease may be dependent on the balance between aortic elastase and antiprotease activity. The dipeptide L-valyl proline (LVP) is a specific amino acid sequence for elastin and can be quantitated by high performance liquid chromatography analysis of the urine. This study was done to determine if alterations in systemic elastin metabolism could be detected in patients with different types of infrarenal aortic disease by quantitating urinary LVP. Patients were divided into one of five groups and had urine analyzed for LVP. These are control, no known aortic disease (n = 12); occlusive aortic disease (n = 10); elective abdominal aortic aneurysms (AAA) (n = 26); ruptured AAA (n = 5), and multiple aneurysms (n = 4). Urine values were correlated with aortic elastase and aortic antiprotease activity. Urinary LVP was significantly higher in patients with multiple aneurysms (1,209 micrograms per milliliter of urine) as compared with all of the other groups. Patients with elective AAA had significantly higher urinary LVP (40.5 micrograms per milliliter of urine) than patients with occlusive disease (9.1 micrograms per milliliter of urine) and those in the control group (4.2 micrograms per milliliter of urine). Patients with ruptured AAA did not have significantly elevated urinary LVP compared with other groups (18.6 micrograms per milliliter of urine). Urinary LVP increased significantly as aortic elastase and aortic elastase and antiprotease activity increased. These data suggest that elastin metabolism, as reflected by urinary LVP, is altered in patients with aortic aneurysmal disease and provide further evidence to support the concept that systemic elastin metabolism is altered in patients with different types of infrarenal aortic pathologic findings.

Topics: alpha 1-Antitrypsin; Aorta, Abdominal; Aortic Aneurysm; Aortic Diseases; Aortic Rupture; Arterial Occlusive Diseases; Chromatography, High Pressure Liquid; Dipeptides; Elastin; Humans; Pancreatic Elastase

Deficiencies of total collagen, type III collagen, and elastin have been proposed to explain aneurysm formation. Infrarenal aortas were collected from 19 patients (age 70 +/- 7 years) undergoing operative repair of abdominal aortic aneurysms (diameter 7 +/- 2 cm) and from 13 autopsies (age 63 +/- 17 years) of patients without aneurysm disease (controls). Wall thickness and collagen and elastin concentration were determined in full-thickness aorta. Collagen types I and III were measured after digestion with cyanogen bromide, which solubilized nearly 90% of total collagen for typing. Cyanogen bromide peptides were separated by sequential carboxymethylcellulose and agarose chromatography and quantified by peak area measurement with computerized image analysis. Histologic examination revealed prominent inflammatory cell infiltration and deficient, fragmented elastin in the aneurysms. Aortic wall thickness was similar in aneurysms and in control specimens. In the aneurysms, collagen was increased (37% +/- 16% vs 24% +/- 5%; p less than 0.05) and elastin was decreased (1% +/- 1% vs 12% +/- 7%; p less than 0.001), expressed as a percentage of delipidized, decalcified dry weight. Collagen type I accounted for 74% +/- 4% of aneurysm and 73% +/- 4% of control collagen solubilized for typing, and collagen type III accounted for 26% +/- 4% of aneurysm and 27% +/- 4% of control collagen solubilized for typing. Neither patients with a family history of aneurysms nor those without a history of aneurysms had collagen type III deficiency. Atherosclerotic abdominal aortic aneurysms are associated with an inflammatory process and may result from elastin degradation and not a deficiency of type III collagen.

Topics: Aged; Amino Acids; Aorta, Abdominal; Aortic Aneurysm; Collagen; Elastin; Female; Histocytochemistry; Humans; Male; Middle Aged

Histochemical studies of nine aneurysmal aortas revealed a conspicuous deficiency of iron hematoxylin-reactive elastin in four specimens, in comparison with eight atherosclerotic control specimens. A fibrillar matrix that morphologically resembled elastin was demonstrated in these same specimens under ultraviolet light. The phenomenon of substantial preservation of features of medial architecture suggests that, if the pathogenetic mechanism is enzymatic destruction, the process is highly selective. Comparisons with differences in human fetal vs newborn aortas and in Blotchy mouse vs normal mouse aortas suggest superficial similarities. These latter observations suggest that a hypothesis of maturation arrest might be considered as an alternative to enzymatic destruction. Definitive experiments to test the relative importance of maturation arrest vs enzymatic destruction in the pathogenesis of aneurysmal disease will require further studies.

Topics: Adult; Animals; Aorta, Abdominal; Aortic Aneurysm; Elastin; Female; Fetal Diseases; Hematoxylin; Histocytochemistry; Humans; Infant, Newborn; Iron; Mice; Pregnancy; Staining and Labeling

Aortic tissue elastase and alpha 1-antitrypsin were assayed in 67 patients with different types of infrarenal aortic disease; occlusive disease, elective abdominal aortic aneurysms (AAAs), multiple aneurysms, and ruptured aneurysms. Elastase modified by alpha 1-antitrypsin (elastase/alpha 1-antitrypsin) increased significantly as the type of aortic disease changed from occlusive to aneurysmal disease. Aortic elastase was significantly higher in patients with AAAs, multiple aneurysms, and ruptured AAAs compared with occlusive disease. The alpha 1-antitrypsin, was significantly lower in patients with multiple aneurysms and ruptured AAAs. These data suggest that the ratio between elastase and its major serum inhibitor, alpha 1-antitrypsin, is significantly altered in the aortic wall in different types of infrarenal aortic disease. In addition, the ratio between these two enzyme systems changes in favor of more proteolytic activity as the type of infrarenal disease changes from occlusive to aneurysmal.

Topics: alpha 1-Antitrypsin; Aorta, Abdominal; Aortic Aneurysm; Aortic Diseases; Aortic Rupture; Arterial Occlusive Diseases; Elastin; Humans; Immunodiffusion; Pancreatic Elastase

Previous studies on the pathogenesis of abdominal aortic aneurysms have shown both elastase-like activity in the aortic wall and a decreased elastin content. The present study, using specific radioimmunoassays for pancreatic elastase 2 (IRE2) and cationic trypsin(ogen) (IRCT), investigates the concentrations of these proteases which are known to circulate in blood, in abdominal aortic aneurysms. Aortic specimens were obtained from 32 patients with aneurysms and 21 patients with atherosclerotic occlusive disease. Aortic tissue, obtained at autopsy from young adults, served as controls. Elastase-like activity was 300% and 800% higher, respectively, in aortic homogenates from aneurysms in comparison to occlusive disease and control aortic tissue. This was associated with 1.4-fold higher level of IRE2 and 2.7-fold higher levels of IRCT as compared to occlusive disease. Although there was no significant difference in the aortic collagen concentration among all 3 groups, the elastin content of aneurysmal aorta was 85% and 74% lower, respectively, in comparison to control and occlusive aorta. The results of this investigation demonstrate the presence of pancreatic elastase 2 and cationic trypsin(ogen) in abdominal aortic aneurysmal tissue and suggest that circulating pancreatic proteases contribute to the pathophysiology of aneurysms of the infrarenal aorta.

Topics: Adult; Aged; Aorta, Abdominal; Aortic Aneurysm; Arteriosclerosis; Elastin; Humans; In Vitro Techniques; Middle Aged; Pancreatic Elastase; Radioimmunoassay; Risk Factors; Smoking; Trypsinogen

Recent evidence indicates that the homeostatic balance between elastase and antiprotease activity is altered in the infrarenal aorta of those patients with different types of aortic pathologic findings. The specific properties of elastase found in the aorta of patients with abdominal aortic aneurysms (AAA) are discussed herein. Activity of elastase extracted from ten pooled AAA specimens was observed when incubated with several inhibitors: 13.2 per cent for phenyl-suphonyl flouride (PSF); 43.3 per cent for ethylenediaminetetraacetic acid (EDTA); 77.7 per cent for pepstatin; 137.0 per cent for leupeptin, and 24.0 per cent for alpha-1-antitrypsin. Irreversible inhibition by PSF indicates that the elastase is a serine protease. The elastase is most likely not a metallo enzyme, since it had no absolute requirement for divalent cations as indicated by only partial inhibition by EDTA. Elastase activity is most likely not due to cathepsins B or D, since cathepsins are active in an acid pH and selectively inhibited by leupeptin and pepstatin. The pH curve revealed a maximum activity at pH 8.2 and elastase activity was significantly inhibited by alpha-1-antitrypsin in a dose response manner determining functional elastase activity. These data indicate that the elastase in the aorta of patients with an AAA has the exact properties of the serine elastase found in the smooth muscle cells of the aorta in rats. These results also confirm the critical role of alpha-1-antitrypsin in determining functional elastase activity. Smooth muscle cell regulation of elastin metabolism may be important in determining why some patients have AAA and others have occlusive aortic disease develop.

Topics: Aorta, Abdominal; Aortic Aneurysm; Elastin; Humans; Muscle, Smooth, Vascular; Pancreatic Elastase; Serine Endopeptidases

Histological sections through the walls of abdominal aortic aneurysms showed scarce and disrupted elastic tissue. The elastin content of the aneurysmal aortic media was only 8.1 +/- 3.2% dry defatted weight (n = 11). The elastin content of grossly normal age and anatomically matched aortic media was 35.0 +/- 3.2% dry weight (n = 4) and the elastin content of severely atherosclerotic, stenosed infrarenal aortic media was 22.0 +/- 7.2% dry weight (n = 6). There was an inverse correlation of elastin content with the elastinolytic activity of aortic media homogenates, r = -0.78. Elastase activity, measured by the hydrolysis of [3H]elastin, was highest in aneurysmal aortic homogenates, 92.1 +/- 43.7 U/mg protein (n = 18), falling to 46.9 +/- 13.3 U/mg protein (n = 13) in severely stenosed atherosclerotic aortic homogenates and 35.5 +/- 11.9 U/mg (n = 6) in grossly normal aortic homogenates. The elastinolytic activity of stenotic aorta contained leukocyte elastase as an important component. In aneurysmal homogenates leukocyte elastase was also found but the increased elastase activity resulted from a protease(s) (Mr 95,000) extracted in 2 M urea, having minimal specificity for alanyl bonds and no immunological cross-reactivity with leukocyte elastase.

Topics: Aged; Amino Acids; Aorta, Abdominal; Aortic Aneurysm; Aortic Valve Stenosis; Elastin; Female; Histocytochemistry; Humans; Male; Middle Aged; Molecular Weight; Pancreatic Elastase; Tissue Extracts

The aortic walls of patients with abdominal aortic aneurysms (AAA) and of healthy controls were examined for elastin, collagen I and III, and the intermediate filament proteins desmin and vimentin by immunohistochemical, enzyme histochemical, and routine histological techniques. The morphology of the aneurysmatic walls varied considerably from case to case, but many pathological changes were seen in all cases, e.g., extensive atherosclerotic plaques in the intima, prominent alterations in amount and organization of the elastic lamellae in the media, and an increase of connective tissue. Both collagen I and III were present in all the aneurysmatic walls. The smooth muscle cells in all the aortic walls showed a marked heterogeneity with respect to the morphological appearance, the enzyme histochemical features, and the content of desmin and vimentin. Vimentin occurred in some intimal, medial muscle, and adventitial cells of both the controls and the AAA patients. Desmin occurred in some of the intimal, medial, and adventitial muscle cells of both the controls and the AAA patients. All the cells with desmin in the intima and media also contained vimentin. Thus, smooth muscle cells in the walls of both the normal human abdominal aorta and aneurysms contained either vimentin, desmin, or both. This variability may be explained by the presence of different phenotypes of smooth muscle cells and could be of significance for the development of atherosclerosis and aneurysms. Of special interest was the finding that 5 of the 24 AAA patients studied had blood relatives with the same disease, suggesting a hereditary influence. However, no systematic differences between the morphological appearance of the aneurysmatic walls in familial and nonfamilial AAA could be detected.

Topics: Aged; Aorta, Abdominal; Aortic Aneurysm; Collagen; Desmin; Elastin; Female; Fluorescent Antibody Technique; Histocytochemistry; Humans; Intermediate Filament Proteins; Male; Middle Aged; Vimentin

Despite significant progress in elucidating the pathogenesis of aneurysmal disease, the precise etiology of arterial wall degradation remains unclear. Numerous etiologies have been implicated, including stress-strain factors, structural wall abnormalities, and enzyme imbalance. We have previously shown that collagenase and elastase are increased in aortic aneurysm tissue. Herein we report and characterize a newly described serum compound that is able to hydrolyze an artificial elastase substrate but is not elastase. This substance is elevated in patients with atherosclerotic disease and, following aneurysmectomy, its concentration increases by threefold. Examination of the substance reveals that it is bound to lipid and consists of four subunits of molecular weights: 310,000, 62,000, 40,000, and 10,000 daltons. It has characteristics of thiol, carboxyl, and metalloenzymes and is most active at a pH of 7.0 to 8.0. A relationship between this serum compound and aneurysm tissue enzymatic activity is noted. We postulate that this serum compound may be produced by mononuclear cells and released into the serum. Furthermore, monocytes may enter the arterial wall intima and release this substance, resulting in proteolytic arterial wall degradation and subsequent aneurysm formation.

Topics: Aortic Aneurysm; Aortic Diseases; Arterial Occlusive Diseases; Blood Proteins; Carotid Artery Diseases; Elastin; Female; Humans; Hydrogen-Ion Concentration; Leukocytes; Male; Middle Aged; Molecular Weight; Monocytes; Neutrophils; Pancreatic Elastase; Peptide Hydrolases; Proteoglycans

An intrinsic defect in the aortic media in six patients with Marfan's syndrome, who died of cardiovascular complications of the disease at an average age of 32 years, has been delineated by correlated morphologic, biochemical, and mechanical studies. The findings in the Marfan aortas have been compared with those in age- and sex-matched controls, who died of unrelated diseases without significant aortic lesions, and in three patients with dissecting aneurysms of non-Marfan origin. The results showed that there was a significant reduction in the tensile strength of the aorta in Marfan's syndrome. This finding was correlated by scanning electron microscopy with structural alterations of the medial elastic fibers, including enlarged interlaminar spaces and loss of interlaminar elastic fibrils. No structural alterations were identified in collagen fibers. Biochemical analyses of the aortic media revealed a substantial reduction in aortic elastin content. Furthermore, the desmosine content of the isolated elastin was reduced by approximately 50%. No changes were detected in the composition or solubility of the medial collagen. In contrast to Marfan aortas, the elastin and collagen contents of the dissecting aneurysms of non-Marfan origin were similar to those of the controls. These findings suggest that the vascular complications in Marfan's syndrome may be based on a genetic abnormality affecting elastin fibrillogenesis.

Topics: Adult; Aorta; Aortic Aneurysm; Aortic Dissection; Collagen; Elastin; Glycosaminoglycans; Humans; Hydroxyproline; Marfan Syndrome; Microscopy, Electron, Scanning; Tensile Strength

Amino acid chromatography was used for determination of the elastin-specific amino acids desmosine and isodesmosine in acid hydrolyzates of intima-medial samples taken intraoperatively from aneurysms of human ascending aorta. Elastin concentration of the specimens was also estimated by hot alkali extraction followed by nitrogen determination of the extracted material and the insoluble residue. All patients studied had annulo-aortic ectasia i.e., dilatation of the aortic annulus and the ascending aorta. Two patients with the Marfan syndrome had low aortic elastin concentration determined by both methods. A third Marfan syndrome patient, youngest of the three, also had a slightly reduced concentration of elastin in the aorta. Aortic samples were studied from five patients who did not have the classical Marfan syndrome. Two patients of those five had decreased aortic elastin concentration. The change in elastin concentration was accompanied by high hydroxyproline/proline or hydroxylysine/lysine ratios which indicates that the proteins of the aneurysmatic aortic wall contained more collagen than the proteins of the control aortic wall. These findings point to a change in the structure or metabolism of elastin in the aortic wall in the Marfan syndrome and at least in some other patients with annulo-aortic ectasia.

Topics: Adolescent; Adult; Amino Acids; Aorta, Thoracic; Aortic Aneurysm; Child; Desmosine; Elastin; Female; Humans; Male; Marfan Syndrome; Middle Aged

Insoluble elastins were isolated from control and aneurytic aortas by a sequential extraction procedure involving the use of purified collagenase. Marked differences in amino acid analyses and susceptibilities to pancreatic elastase were observed between normal and pathological samples. The incorporation of either 14C-lysine or 14C-glucosamine into proteins of the vessel wall was also studied. In addition, high amounts of elastase-type activity was extractable from pathological aorta specimens which may contribute significantly to the loss of elastic tissue evidenced by ultra-structural studies and confirmed by the biochemical technics. We propose therefore that increased elastase-type protease activity in these pathological aortas does significantly contribute to the weakening of the aortic wall and also may well be the main cause of the rupture of aneurysms observed occasionally.

Topics: Adult; Aged; Aorta; Aortic Aneurysm; Aortic Dissection; Elastic Tissue; Elastin; Female; Humans; Hydrolysis; Male; Marfan Syndrome; Middle Aged; Muscle, Smooth, Vascular; Organ Culture Techniques; Pancreatic Elastase

Beta-amino-propionitrile was administered in a single dose into the chorioallantoic cavity of 14 days old chick embryos. The effects on the elastic fibre production were examined on the 3rd or 7th day following the injection. By light microscopy dissecting aneurysm, aortic ruptures were found. The elastic fibres were poorly developed and exhibited irregularities and structural anomalies. Electron microscopically we observed reduction of the number or complete absence of elastic aggregates and fibres. The elastic structures exhibited abnormal phosphotungstic acid binding. This was considered as a sign for disturbances in the development of cross linkages and in the incorporation of elastin into the elastic fibres.

Topics: Aminopropionitrile; Animals; Aorta; Aortic Aneurysm; Aortic Rupture; Chick Embryo; Elastic Tissue; Elastin; Phosphotungstic Acid

A genetic abnormality in collagen and elastin cross-linking resembling experimental lathyrism has been identified in mice. The defect is an X-linked trait, attributed to the mottled locus which also influences coat color. The affected mice have aneurysms of the aorta and its branches, weak skin, and bone deformities in a spectrum of severity varying with the alleles at the mottled locus. A defect in the cross-linking of collagen was demonstrated in the skin of the affected animals by a marked increase in collagen extractability and a reduced proportion of cross-linked components in the extracted collagen. A decrease in lysine-derived aldehyde levels was found in both skin collagen and aortic elastin similar to that found in lathyritic tissue. Furthermore the in vitro formation of lysine-derived aldehyde was reduced. Thus the cause of the connective tissue abnormalities in these mice appears to be a defect in cross-link formation due to an impairment in aldehyde formation.

Topics: Animals; Aortic Aneurysm; Bone and Bones; Collagen; Elastin; Female; Genes; Genetic Linkage; Male; Mice; Sex Chromosome Aberrations; Skin; Skin Abnormalities

Topics: Aged; Aorta, Abdominal; Aortic Aneurysm; Aortic Rupture; Arteriosclerosis; Biomechanical Phenomena; Collagen; Elasticity; Elastin; Humans; Iliac Artery; Mesenteric Arteries; Middle Aged; Pressure; Proteins; Renal Artery

Topics: Amino Acids; Animals; Aorta, Thoracic; Aortic Aneurysm; Ceruloplasmin; Collagen; Copper; Elastin; Female; Histocytochemistry; Lathyrism; Lysine; Male; Rats

Topics: Alkaline Phosphatase; Animals; Aorta; Aortic Aneurysm; Collagen; Elastin; Fumarates; Glycosaminoglycans; Histocytochemistry; Lathyrism; Male; Microscopy, Electron; Muscle, Smooth; Rats

Topics: Aminopropionitrile; Aorta; Aortic Aneurysm; Chemical Phenomena; Chemistry; Collagen; Cyanides; Elastin; Histological Techniques; Lathyrism; Pathology; Rats; Research