elastin and Arterial-Occlusive-Diseases

The large and medium-sized arteries in elderly people show varying degrees of intimal and medial change. The medial change is known as age-related medial degeneration and sclerosis (ARMDS). The ARMDS results in systolic hypertension and left ventricular hypertrophy of the heart as a result of loss of arterial elasticity. It also causes aortic dilatation, or even aortic aneurysm. The ARMDS and atherosclerosis are distinct entities, but are often overlapped and confused with each other. The present review mainly focuses on ARMDS and briefly addresses atherosclerosis, and aging of arterioles, capillaries and veins. The smooth muscle cells in the inner half of the aortic media of elderly people degenerate and undergo apoptosis. This causes degradation of elastin fibers and the accumulation of collagen fibers in the media, but the inflammatory infiltrates are scarce. Biochemical studies showed an age-related decrease of elastin and its crosslinks, and an increase of collagen and its crosslink. Because the turnover of elastin is very long, it likely suffers from glycation (Maillard reaction) and glyco-oxidative reaction. The advanced glycation end-products accumulate in the aortic media with increasing age. Alcian-blue positive mucin accumulates in aortic media in elderly people. The major component of the increase of aortic mucin is chondroitin-6-sulfate. Microcalcification is frequent in the inner acellular portion of the aortic media in elderly people. Calcium contents increase with age. In conclusion, the ARMDS is a distinct pathological entity with clinical significance. The pathogenesis of ARMDS is unclear; the mechanical stress of elastin, endothelial dysfunction, and glycation of elastin are proposed.

Topics: Aging; Arterial Occlusive Diseases; Arteries; Atherosclerosis; Capillaries; Collagen; Dilatation, Pathologic; Disease Progression; Elasticity; Elastin; Endothelium, Vascular; Glycation End Products, Advanced; Glycosaminoglycans; Humans; Immunohistochemistry; Microfibrils; Sclerosis; Tunica Media

Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells-derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in rescuing the SMC phenotype in elastin insufficiency patients. Approach and Results: SMCs generated from induced pluripotent stem cells from 5 elastin insufficiency patients with severe recurrent vascular stenoses (3 Williams syndrome and 2 elastin mutations) were phenotypically immature, hyperproliferative, poorly responsive to endothelin, and exerted reduced tension in 3-dimensional smooth muscle biowires. Elastin mRNA and protein were reduced in SMCs from patients compared to healthy control SMCs. Fourteen drug candidates were tested on patient SMCs. Of the mammalian target of rapamycin inhibitors studied, everolimus restored differentiation, rescued proliferation, and improved endothelin-induced calcium flux in all patient SMCs except one Williams syndrome. Of the calcium channel blockers, verapamil increased SMC differentiation and reduced proliferation in Williams syndrome patient cells but not in elastin mutation patients and had no effect on endothelin response. Combination treatment with everolimus and verapamil was not superior to everolimus alone. Other drug candidates had limited efficacy.. Everolimus caused the most consistent improvement in SMC differentiation, proliferation and in SMC function in patients with both syndromic and nonsyndromic elastin insufficiency, and offers the best candidate for drug repurposing for treatment of elastin insufficiency associated vasculopathy.

Topics: Arterial Occlusive Diseases; Case-Control Studies; Cell Differentiation; Cell Line; Cell Proliferation; Constriction, Pathologic; Elastin; Everolimus; Female; Heterozygote; Humans; Induced Pluripotent Stem Cells; Infant; Male; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Phenotype; Protein Kinase Inhibitors; TOR Serine-Threonine Kinases; Williams Syndrome

Topics: Aortic Diseases; Aortic Stenosis, Supravalvular; Arterial Occlusive Diseases; Elastin; Humans; Williams Syndrome

A persistent clinical demand exists for a suitable arterial prosthesis. In this study, a vascular conduit mimicking the native 3-layered artery, and constructed from the extracellular matrix proteins type I collagen and elastin, was evaluated for its performance as a blood vessel equivalent. A tubular 3-layered graft (elastin-collagen-collagen) was prepared using highly purified type I collagen fibrils and elastin fibers, resembling the 3-layered native blood vessel architecture. The vascular graft was crosslinked and heparinised (37 ± 4 μg heparin/mg graft), and evaluated as a vascular graft using a porcine bilateral iliac artery model. An intra-animal comparison with clinically-used heparinised ePTFE (Propaten®) was made. Analyses included biochemical characterization, duplex scanning, (immuno)histochemistry and scanning electron microscopy. The tubular graft was easy to handle with adequate suturability. Implantation resulted in pulsating grafts without leakage. One week after implantation, both ePTFE and the natural acellular graft had 100% patencies on duplex scanning. Grafts were partially endothelialised (Von Willebrand-positive endothelium with a laminin-positive basal membrane layer). After one month, layered thrombi were found in the natural (4/4) and ePTFE graft (1/4), resulting in occlusion which in case of the natural graft is likely due to the porosity of the inner elastin layer. In vivo application of a molecularly-defined tubular graft, based on nature's matrix proteins, for vascular surgery is feasible.

Topics: Animals; Arterial Occlusive Diseases; Bioprosthesis; Blood Vessel Prosthesis; Collagen; Elastin; Equipment Failure Analysis; Extracellular Matrix Proteins; Female; Graft Rejection; Iliac Artery; Prosthesis Design; Swine; Treatment Outcome; Vascular Grafting; Vascular Patency

Patients with elastin deficiency attributable to gene mutation (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) are characterized by obstructive arteriopathy resulting from excessive smooth muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We investigated whether rapamycin, an inhibitor of the cell growth regulator mammalian target of rapamycin (mTOR) and effective against other SMC proliferative disorders, is of therapeutic benefit in experimental models of elastin deficiency.. As previously reported, Eln(-/-) mice demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas Eln(+/-) mice exhibited a smaller diameter aorta with more numerous but thinner elastic lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of newborn pups that was inhibited by maternal administration of rapamycin. mTOR inhibition reduced SMC proliferation and aortic obstruction in Eln(-/-) pups and prevented medial hyperlamellation in Eln(+/-) weanlings without compromising aortic size. However, rapamycin did not prolong the survival of Eln(-/-) pups, and it retarded the somatic growth of juvenile Eln(+/-) and Eln(+/+) mice. In cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced proliferation of SMC derived from patients with supravalvular aortic stenosis and with Williams syndrome.. mTOR inhibition may represent a pharmacological strategy to treat diffuse arteriopathy resulting from elastin deficiency.

Topics: Adult; Animals; Aortic Stenosis, Supravalvular; Arterial Occlusive Diseases; Cell Proliferation; Elastin; Female; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Williams Syndrome

We present a 3-year-old boy with an elastin gene mutation and multiple peripheral pulmonary stenoses, who developed aneurysms of the pulmonary arteries spontaneously. We performed transcatheter occlusion of the aneurysms with detachable coils. While pulmonary arterial aneurysms may develop following pulmonary balloon angioplasty, spontaneous development is exceedingly rare. To the best of our knowledge, this is the first report describing spontaneous development of pulmonary artery aneurysms in a patient with peripheral pulmonary artery stenoses due to mutation of the elastin gene or Williams-Beuren syndrome.

Topics: Aneurysm, Ruptured; Angiography; Arterial Occlusive Diseases; Cardiac Catheterization; Child, Preschool; DNA; Elastin; Embolization, Therapeutic; Follow-Up Studies; Humans; Male; Mutation; Pulmonary Artery; Rupture, Spontaneous; Tomography, X-Ray Computed; Williams Syndrome

Vascular tissue engineering has emerged as a promising technology for the design of an ideal, responsive, living conduit with properties similar to that of native tissue. The missing link in tissue-engineered blood vessels is elastin biosynthesis. Several biomaterials are currently used but few support elastin biosynthesis in a 3-D array. In previous studies, we demonstrated that a hyaluronan-based scaffold (HYAFF-11) grafted in the infrarenal rat aorta successfully guided the complete regeneration of a well-functioning small-diameter (2 mm) neoartery. The aim of the present study was to test the ability of HYAFF-11 biodegradable grafts to develop into neovessels of larger size (4 mm) in a porcine model, focusing on extracellular matrix (ECM) remodeling and elastin biosynthesis. HYAFF-11 tubes (diameter 4 mm, length 5 cm) were implanted in an end-to-end fashion in the common carotid artery. Grafts were analyzed for patency with a Duplex scan every 15 days. ECM components were evaluated by histological and molecular biological methods. All the animals survived the observation period without complications. Intimal hyperplasia (initiating at the anastomotic site) and graft thrombosis led to 3 cases of partial or complete occlusion, as demonstrated by histological examination. There were no signs of stenoses or aneurysms in the remaining grafts. After 5 months, the biomaterial was almost completely degraded and replaced by a neoartery segment composed of mature smooth muscle cells, collagen, and elastin fibers organized in layers and was completely covered on the luminal surface by endothelial cells (vWF(+)). Whereas in previous small animal studies, patency rates were not optimal, those obtained in the present study using hyaluronan-based grafts of larger size confirmed the ability of these constructs to guide the development of a well-functioning neoartery, with the remarkable additional attribute of facilitating the formation of organized layers of elastin fibers.

Topics: Animals; Arterial Occlusive Diseases; Base Sequence; Biocompatible Materials; Bioprosthesis; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Carotid Artery, Common; DNA Primers; Elastin; Extracellular Matrix; Gene Expression; Hyaluronic Acid; Materials Testing; Sus scrofa; Tissue Engineering

Seminal to the process of arterial restenosis after balloon angioplasty is extracellular matrix degradation by metalloproteinases (MMPs); activity of these proteins is strongly inhibited by the tissue inhibitors of MMPs (TIMPs). Here we exploit gene transfer using an adeno-associated virus (AAV) for TIMP1 gene delivery in a rat model of intimal hyperplasia. High-titer AAV-Timp1 efficiently transduced human coronary artery smooth muscle cells (SMCs) in vitro and inhibited the capacity of these cells to migrate through a Matrigel barrier. In injured rat carotid arteries, AAV vectors were found to transduce SMCs efficiently and to maintain transgene expression for several weeks in vivo. In AAV-Timp1-transduced animals, the intima:media ratio of injured carotids was significantly reduced by 70.5% after 2 weeks, by 58.5% after 1 month, and by 52.4% after 2 months from treatment. The decrease in intimal hyperplasia was paralleled by a significant inhibition of collagen accumulation and by increased elastin deposition in the neointima, two findings that relate to the inhibition of MMP activity. These results indicate that AAV vectors are efficient tools for delivering genes to the arterial wall and emphasize the importance of MMPs for the generation of intimal hyperplasia. Local TIMP1 gene transfer might thus represent an efficient strategy to prevent restenosis.

Topics: Angioplasty, Balloon; Animals; Arterial Occlusive Diseases; Carotid Arteries; Collagen; Dependovirus; Elastin; Genetic Therapy; Genetic Vectors; Humans; Hyperplasia; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Muscle, Smooth, Vascular; Rats; Tissue Inhibitor of Metalloproteinase-1; Transfection; Tunica Intima

To measure serum concentrations of elastin-derived peptides (S-EDP) in patients with aneurysmal, occlusive and ulcerative manifestations of atherosclerotic disease.. S-EDP concentrations were measured by a competitive enzyme-linked immunosorbent assay in 10 patients with infrarenal aneurysms 5cm in diameter (AAA), 10 patients with distal aortic occlusive disease (AOD), 10 patients with symptomatic carotid stenosis (>or=70%) and plaque ulceration (SCS) and a control group of 10 patients with no similar specific manifestations of atherosclerotic disease (NAM).. S-EDP concentrations (median, range) were significantly higher in patients with AAA (42ng/ml, 35-52, p<0.001) and SCS (49ng/ml, 37-60, p<0.001) but not AOD (28ng/ml, 22-38, p=0.240) compared to NAM (26ng/ml, 19-36) patients.. Increased concentrations of S-EDP were associated with aneurysmal and ulcerative, but not occlusive, manifestations of atherosclerosis.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Aortic Aneurysm, Abdominal; Aortic Diseases; Arterial Occlusive Diseases; Arteriosclerosis; Carotid Stenosis; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Peptides; Pulmonary Disease, Chronic Obstructive; Smoking; Statistics, Nonparametric

Vulnerable plaque generally contains a thin fibrous cap, lipid pools, and reduced internal plaque collagen. Arterial fluorescence analysis can differentiate atherosclerotic lesions from normal arteries; however, the contribution of the lipid core to atherosclerotic arterial fluorescence remains controversial. This study aimed to identify lipid core fluorophores and to differentiate the lipid core from normal artery and atheroma. The helium-cadmium laser-induced fluorescence spectra of cadaveric arteries and known chemical constituents were recorded. Lipid core fluorescence spectra exhibited marked red shifts and broadening compared with the fluorescence spectra of normal tissue and atheroma. Similar fluorescence spectra were obtained for lipid core and oxidized low density lipoprotein, for atheroma and collagen, and for normal artery and elastin. A classification based on collagen, elastin, and oxidized low density lipoprotein spectral decomposition could discriminate the lipid core (n=29), normal artery (n=74), atheroma (n=73), and preatheroma (n=10) with 86% accuracy. Fibrous cap thickness was correlated with the spectral collagen content index (r=0.65, P<0.0001), especially at a thickness of <200 microm. We conclude that a classification algorithm based on chemical spectral decomposition can accurately classify the fluorescence spectra of normal artery, atheroma, and lipid core and may be useful in identifying vulnerable atheroma in vivo.

Topics: Adult; Algorithms; Arterial Occlusive Diseases; Cadaver; Collagen; Coronary Artery Disease; Elastin; Femoral Artery; Humans; Lasers; Lipids; Lipoproteins, LDL; Microscopy, Fluorescence; Oxidation-Reduction

Local intracoronary delivery of recombinant adenoviruses expressing anti-migratory or anti-proliferative proteins including human constitutive endothelial nitric oxide synthase (NOS3), plasminogen activator inhibitor 1 (PAI-1), or herpesvirus thymidine kinase (TK) (combined with ganciclovir) was used to prevent neointimal formation in porcine coronary arteries. After balloon injury of the left anterior descending (LAD) coronary artery, animals received an intramural injection of adenovirus (1.5 X 10(9) PFU) carrying either the NOS3 cDNA (AdCMVNOS3, n = 12), the PAI-1 cDNA (AdCMVPAI-1, n = 12), the TK cDNA (AdMLPItk, n = 12), or no cDNA (AdpL+, n = 12). After 28 days, morphometric analysis was performed on coronary sections from all segments demonstrating injury. The internal elastic lamina (IEL) fracture length normalized to the IEL perimeter (initial injury) and the neointimal area normalized to the vessel area (response to injury) were used to generate linear regression lines and calculate an index of stenosis for the respective treatment groups. The response to injury was significantly smaller in AdCMVNOS3- and AdMLPItk-infected animals than in AdpL+-infected animals (slopes = 0.86 +/- 0.05 and 0.69 +/- 0.07 versus 1.11 +/- 0.06, p < 0.005 and p < 0.0001, respectively) but not in AdCMVPAI-1-infected animals (slope = 1.26 +/- 0.04, p = 0.04). No viral shedding was observed and there was no acute systemic toxicity after gene transfer. An increase in neutralizing antibody titers against Ad vectors was observed without any detectable response to the transgene products (NOS3, PAI-1). Local gene transfer of NOS3 and TK may hold promise as a safe and effective adjunctive treatment to reduce neointimal formation after percutaneous coronary intervention in humans.

Topics: Adenoviruses, Human; Angioplasty, Balloon, Coronary; Animals; Antibodies, Viral; Arterial Occlusive Diseases; Coronary Vessels; Elastin; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Herpesvirus 1, Human; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Plasminogen Activator Inhibitor 1; Swine; Thymidine Kinase

Elastin, the main component of the extracellular matrix of arteries, was thought to have a purely structural role. Disruption of elastin was believed to lead to dissection of arteries, but we showed that mutations in one allele encoding elastin cause a human disease in which arteries are blocked, namely, supravalvular aortic stenosis. Here we define the role of elastin in arterial development and disease by generating mice that lack elastin. These mice die of an obstructive arterial disease, which results from subendothelial cell proliferation and reorganization of smooth muscle. These cellular changes are similar to those seen in atherosclerosis. However, lack of elastin is not associated with endothelial damage, thrombosis or inflammation, which occur in models of atherosclerosis. Haemodynamic stress is not associated with arterial obstruction in these mice either, as the disease still occurred in arteries that were isolated in organ culture and therefore not subject to haemodynamic stress. Disruption of elastin is enough to induce subendothelial proliferation of smooth muscle and may contribute to obstructive arterial disease. Thus, elastin has an unanticipated regulatory function during arterial development, controlling proliferation of smooth muscle and stabilizing arterial structure.

Topics: Animals; Aorta; Arterial Occlusive Diseases; Arteries; Arteritis; Cell Line; Elastin; Embryonic and Fetal Development; Female; Hemodynamics; Male; Mice; Mice, Inbred C57BL; Morphogenesis; Muscle Development; Muscle, Smooth, Vascular; Mutagenesis; Neovascularization, Physiologic; Organ Culture Techniques; Stem Cells

Obstructive vascular disease is an important health problem in the industrialized world. Through a series of molecular genetic studies, we demonstrated that loss-of-function mutations in one elastin allele cause an inherited obstructive arterial disease, supravalvular aortic stenosis (SVAS). To define the mechanism of elastin's effect, we generated mice hemizygous for the elastin gene (ELN +/-). Although ELN mRNA and protein were reduced by 50% in ELN +/- mice, arterial compliance at physiologic pressures was nearly normal. This discrepancy was explained by a paradoxical increase of 35% in the number of elastic lamellae and smooth muscle in ELN +/- arteries. Examination of humans with ELN hemizygosity revealed a 2. 5-fold increase in elastic lamellae and smooth muscle. Thus, ELN hemizygosity in mice and humans induces a compensatory increase in the number of rings of elastic lamellae and smooth muscle during arterial development. Humans are exquisitely sensitive to reduced ELN expression, developing profound arterial thickening and markedly increased risk of obstructive vascular disease.

Topics: Animals; Aorta; Arterial Occlusive Diseases; Blotting, Northern; Compliance; Elastin; Humans; Mice; Mice, Knockout; Microscopy, Electron; Tunica Media

The purpose of this study was to characterize the distribution of aortic wall microvessels in normal aorta, atheroocclusive disease (AOD), and abdominal aortic aneurysms (AAA) and to evaluate whether medial neovascularization (MNV) is a reliable histopathologic marker of aneurysmal degeneration.. Aortic tissue specimens (9 normal, 10 AOD, and 10 AAA) were examined for elastin with Verhoeff-van Gieson stain and for Ulex europaeus type I lectin, an endothelial-specific antigen, and laminin, a marker of basement membranes, by immunohistochemistry. The density of MNV was determined by morphometry of aortic sections stained for endothelium. The spatial distribution of aortic microvessels was compared with that of elastin destruction and chronic inflammation.. Evidence of medial neovascularization was generally not observed in normal aorta or AOD, whereas AAAs showed strong spatial correlations between MNV, disruption and degradation of elastin, and chronic inflammation in the outer aortic wall. Several specimens of AOD had focal areas of MNV associated with localized elastin fragmentation and monocytic infiltration located at the interface between the atherosclerotic plaque and the inner media. The density of MNV was about fifteenfold higher in AAA compared with normal aorta and about threefold higher compared with AOD (microvessels per high-power field): normal aorta, 0.77 +/- 0.28; AOD, 3.40 +/- 0.51; AAA, 11.32 +/- 1.58 (ANOVA, p < 0.001).. The presence and density of MNV in the abdominal aorta is a consistent histopathologic marker of aneurysmal degeneration that is spatially correlated with the destruction of elastin and chronic inflammation. The observation of focal MNV in some specimens of AOD, associated with partial elastin disruption, raises the possibility that early changes of aneurysm disease might develop by an extension of angiogenic/inflammatory processes from the atherosclerotic plaque into the aortic media.

Topics: Adult; Aged; Analysis of Variance; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Arterial Occlusive Diseases; Arteriosclerosis; Elastin; Endothelium, Vascular; Female; Humans; Immunohistochemistry; Laminin; Lectins; Male; Middle Aged; Neovascularization, Pathologic; Tunica Media

An antibody to elastin-derived chemotactic peptide Val-Gly-Val-Ala-Pro-Gly was used to study human artery samples from 18 patients with various vascular lesions, such as aneurysms or occlusive arteriopathy. The antibody recognised epitopes in two artery specimens, one occlusive arteriopathy and one aneurysm, and both specimens were also characterised by a segmental destruction of media. The positive staining for the peptide was located in the elastic membranes and endothelial cells that were also stained with antibodies to IgG. This study suggests that elastin-derived chemotactic peptides may have a role in vascular lesions characterised by a destruction of media and a formation of aneurysm. Since elastin-derived chemotactic peptides are more chemotactic to monocytes than to neutrophils, it is possible that mononuclear phagocytes are involved in the segmental destruction of elastin.

Topics: Adult; Aged; Aortic Aneurysm, Abdominal; Aortic Dissection; Arterial Occlusive Diseases; Arteries; Arteriosclerosis; Arteritis; Chemotactic Factors; Elastic Tissue; Elastin; Endothelium, Vascular; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Peptides; Tunica Media; Vascular Diseases

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

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

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

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

Fibromuscular dysplasia (FMD) was found in 24 of 31 turkeys studied. This is the first species other than man in which FMD has been reported. FMD in turkeys simulates lesions variously known as fibromuscular dysplasia, fibromuscular hyperplasia, and medial hyperplasia in man. It occurred in turkeys from 8 weeks to 1 year of age and was evenly distributed between the sexes (11 males, 13 females). FMD in turkeys is a disease of arterioles and small arteries 44 mu to 666 mu in diameter. A lesion of more than 2.6 mm in length (in an artery 0.1 mm in diameter) was encountered. An adherent thrombus over 670 mu long was seen attached to an FMD lesion. Angiopathy appears to be basic to the pathogenesis of FMD and is characterized by endothelial hyperplasia, smooth-muscle vacuolization, and patchy necrosis of the media.

Topics: Animals; Arterial Occlusive Diseases; Arteries; Disease Models, Animal; Elastin; Female; Fibromuscular Dysplasia; Male; Muscles; Musculoskeletal System; Turkeys

Topics: Animals; Arterial Occlusive Diseases; Collagen; Dilatation; Dogs; Elasticity; Elastin; Hydrogen-Ion Concentration; Hydrostatic Pressure; In Vitro Techniques; Jugular Veins; Lactates; Microbial Collagenase; Pancreatic Elastase; Sodium Chloride; Solutions; Stress, Mechanical; Temperature; Tissue Preservation; Veins

Topics: Age Factors; Animals; Aorta; Aorta, Thoracic; Arterial Occlusive Diseases; Arteries; Blood Pressure; Cardiovascular System; Carotid Arteries; Cerebral Arteries; Chick Embryo; Collagen; Connective Tissue; DNA; Elastic Tissue; Elastin; Female; Gestational Age; Humans; Male; Rats; RNA; Vascular Resistance