elastin and Cardiomegaly

Extracellular matrix (ECM) in the heart and vascular wall includes fibrous proteins and proteoglycans. Fibrous proteins are classified within two categories: structural (collagen and elastin) and adhesive molecules (laminin and fibronectin). These ECM components are important in maintenance of both structure and function of the heart and vascular tissues. Myocardial infarction, hypertrophy, hypertension and heart failure are well known to be associated with progressive cardiac fibrosis. Vascular hypertrophy and thickening has been associated with the pathological series of events that attends both hypertension and restenosis. The accumulation of ECM in the cardiovascular system plays an important role in the development of heart failure after myocardial infarction and hypertension, as well as in vascular hypertrophy and restenosis. Angiotensin II (angiotensin) and transforming growth factor beta 1 are known to play a role in signalling the abnormal accumulation of ECM in these cardiovascular diseases. Administration of angiotensin-converting enzyme inhibitor or angiotensin receptor type 1 antagonist is associated with regression of cardiac hypertrophy and fibrosis as well as vascular hypertrophy.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Cardiomegaly; Cardiovascular Diseases; Collagen; Elastin; Extracellular Matrix; Fibronectins; Heart Failure; Humans; Myocardial Infarction; Proteoglycans

The cardiac interstitium is populated by nonmyocyte cell types including transcriptionally active cardiac fibroblasts and endothelial cells. Since these cells are the source of many components of the cardiac extracellular matrix, and because changes in cardiac extracellular matrix are suspected of contributing to the genesis of cardiovascular complications in disease states such as diabetes, hypertension, cardiac hypertrophy and congestive heart failure, interest in the mechanisms of activation of fibroblasts and endothelial cells has led to progress in understanding these processes. Recent work provides evidence for the role of the renin-angiotensin-aldosterone system in the pathogenesis of abnormal deposition of extracellular matrix in the cardiac interstitium during the development of inappropriate cardiac hypertrophy and failure. The cardiac extracellular matrix is also known to change in response to altered cardiac performance associated with post-natal aging, and in response to environmental stimuli including intermittent hypoxia and abnormal nutrition. It is becoming clear that the extracellular matrix mainly consists of molecules of collagen types I and III; they form fibrils and provide most of the connective material for typing together myocytes and other structures in the myocardium and thus is involved in the transmission of developed mechanical force. The data available in the literature support the view that the extracellular matrix is a dynamic entity and alterations in this structure result in the development of heart dysfunction.

Topics: Cardiomegaly; Chemical Fractionation; Collagen; Elastin; Extracellular Matrix Proteins; Glycosylation; Heart; Heart Failure; Humans

Hypertension-induced cardiac hypertrophy is one of the most common pre-conditions that accompanies heart failure. This study aimed to identify the key pathogenic genes in the disease process.. GSE18224 was re-analyzed and differentially expressed genes (DEGs) were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out. Networks of transcription factor (TF)-mRNA, microRNA (miRNA)-mRNA and Protein-Protein interaction (PPI) were constructed, and a key module was further screened out from PPI network. GSE36074 dataset and our transverse aortic constriction (TAC) mouse model were used to validate gene expression in the module. Finally, the correlation between the genes and biomarkers of cardiac hypertrophy were evaluated.. Totally, there were 348 DEGs in GSE18224, which were mainly enriched in biological processes including collagen fibril organization, cellular response to transforming growth factor-beta stimulus and were involved in ECM-receptor interaction and Oxytocin signaling pathway. There were 387 miRNAs targeted by 257 DEGs, while 177 TFs targeted 71 DEGs. The PPI network contained 222 nodes and 770 edges, with 18 genes screened out into the module. After validation, 8 genes, which were also significantly upregulated in the GSE36074 dataset, were selected from the 18 DEGs. 2 of the 8 DEGs, including Eln and Tgfb3 were significantly upregulated in our mouse model of myocardial hypertrophy. Finally, the expression of Eln and Tgfb3 were found to be positively correlated with the level of the disease biomarkers.. Upregulated key genes Eln and Tgfb3 were positively correlated with the severity of cardiac hypertrophy, which may provide potential therapeutic targets for the disease.

Topics: Animals; Biomarkers; Cardiomegaly; Elastin; Gene Expression Profiling; Gene Regulatory Networks; Mice; MicroRNAs; RNA, Messenger; Transforming Growth Factor beta3; Up-Regulation

There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G(+/-)) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE(-/-)) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE(-/-)Fbn1(C1039G+/-) mice and was associated with myocardial infarction, stroke, and sudden death.. Female ApoE(-/-)Fbn1(C1039G+/-) and ApoE(-/-) mice were fed a WD for up to 35 weeks. Compared to ApoE(-/-) mice, plaques of ApoE(-/-)Fbn1(C1039G+/-) mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE(-/-)Fbn1(C1039G+/-) mice. In ApoE(-/-) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(-/-)Fbn1(C1039G+/-) mice died suddenly, whereas all ApoE(-/-) mice survived. ApoE(-/-)Fbn1(C1039G+/-) mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke.. Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE(-/-)Fbn1(C1039G+/-) mice represent a unique model of acute plaque rupture with human-like complications.

Topics: Animals; Aorta; Apolipoproteins E; Biomarkers; Brachiocephalic Trunk; Cardiomegaly; Carotid Artery, Common; Cerebrovascular Circulation; Death, Sudden; Diet, Western; Disease Models, Animal; Elastin; Female; Fibrillin-1; Fibrillins; Hemorrhage; Hypoxia, Brain; Mice; Microfilament Proteins; Microvessels; Myocardial Infarction; Neovascularization, Pathologic; Nervous System Diseases; Plaque, Atherosclerotic; Rupture, Spontaneous; Stroke; Ventricular Dysfunction, Left

Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S(-/-)), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S(-/-) and Ltbp4-null (Ltbp4(-/-)) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C.

Topics: Animals; Animals, Newborn; Aorta; Cardiomegaly; Cutis Laxa; Elastic Tissue; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Female; Gene Silencing; Genes, Recessive; Glycosylation; Heart Ventricles; Humans; Latent TGF-beta Binding Proteins; Lung; Mice, Inbred C57BL; Models, Biological; Protein Binding; Protein Isoforms; Skin; Weight Loss

A hallmark feature of Williams-Beuren Syndrome (WBS) is a generalized arteriopathy due to elastin deficiency, presenting as stenoses of medium and large arteries and leading to hypertension and other cardiovascular complications. Deletion of a functional NCF1 gene copy has been shown to protect a proportion of WBS patients against hypertension, likely through reduced NADPH-oxidase (NOX)-mediated oxidative stress. DD mice, carrying a 0.67 Mb heterozygous deletion including the Eln gene, presented with a generalized arteriopathy, hypertension, and cardiac hypertrophy, associated with elevated angiotensin II (angII), oxidative stress parameters, and Ncf1 expression. Genetic (by crossing with Ncf1 mutant) and/or pharmacological (with ang II type 1 receptor blocker, losartan, or NOX inhibitor apocynin) reduction of NOX activity controlled hormonal and biochemical parameters in DD mice, resulting in normalized blood pressure and improved cardiovascular histology. We provide strong evidence for implication of the redox system in the pathophysiology of the cardiovascular disease in a mouse model of WBS. The phenotype of these mice can be ameliorated by either genetic or pharmacological intervention reducing NOX activity, likely through reduced angII-mediated oxidative stress. Therefore, anti-NOX therapy merits evaluation to prevent the potentially serious cardiovascular complications of WBS, as well as in other cardiovascular disorders mediated by similar pathogenic mechanism.

Topics: Acetophenones; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Arteries; Blood Pressure; Cardiomegaly; Constriction, Pathologic; Disease Models, Animal; Elastin; Enzyme Activation; Enzyme Inhibitors; Humans; Hypertension; Losartan; Mice; NADPH Oxidases; Oxidative Stress; Sequence Deletion; Williams Syndrome

After a myocardial infarction, thinning and expansion of the fibrotic scar contribute to progressive heart failure. The loss of elastin is a major contributor to adverse extracellular matrix remodelling of the infarcted heart, and restoration of the elastic properties of the infarct region can prevent ventricular dysfunction. We implanted cells genetically modified to overexpress elastin to re-establish the elastic properties of the infarcted myocardium and prevent cardiac failure. A full-length human elastin cDNA was cloned, subcloned into an adenoviral vector and then transduced into rat bone marrow stromal cells (BMSCs). In vitro studies showed that BMSCs expressed the elastin protein, which was deposited into the extracellular matrix. Transduced BMSCs were injected into the infarcted myocardium of adult rats. Control groups received either BMSCs transduced with the green fluorescent protein gene or medium alone. Elastin deposition in the infarcted myocardium was associated with preservation of myocardial tissue structural integrity (by birefringence of polarized light; P < 0.05 versus controls). As a result, infarct scar thickness and diastolic compliance were maintained and infarct expansion was prevented (P < 0.05 versus controls). Over a 9-week period, rats implanted with BMSCs demonstrated better cardiac function than medium controls; however, rats receiving BMSCs overexpressing elastin showed the greatest functional improvement (P < 0.01). Overexpression of elastin in the infarcted heart preserved the elastic structure of the extracellular matrix, which, in turn, preserved diastolic function, prevented ventricular dilation and preserved cardiac function. This cell-based gene therapy provides a new approach to cardiac regeneration.

Topics: Adenoviridae; Animals; Cardiomegaly; Cicatrix; Cloning, Molecular; Diastole; Elastin; Extracellular Matrix; Female; Genetic Therapy; Genetic Vectors; Heart; Heart Failure; Mesenchymal Stem Cells; Myocardial Infarction; Organisms, Genetically Modified; Rats; Rats, Inbred Lew

Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF). Real-time PCR and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV tissues was greater in rats or humans with HF than in those with hypertrophy or in control subjects. Immunostaining showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cells, but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LV intramyocardial coronary arteries of HF rats. The amount of elastolytic activity in the extract of the LV myocardium was markedly increased for HF rats compared with controls, and this activity was mostly because of cathepsin S. Although the amount of elastin mRNA was increased in the LV myocardium of HF rats, the area of interstitial elastin was not. The expression of interleukin 1beta was increased in the LV myocardium of HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes. These results suggest that cathepsin S participates in pathological LV remodeling associated with hypertension-induced HF. This protease is, thus, a potential target for therapeutics aimed at preventing or reversing cardiac remodeling.

Topics: Adult; Aged; Animals; Cardiomegaly; Cathepsins; Elastin; Enzyme Activation; Heart Failure; Humans; Hydrolysis; Hypertension; Male; Middle Aged; Myocardium; Rats; Rats, Inbred Dahl; Up-Regulation

We report three pregnancies where enlarged nuchal translucency was discovered at the first trimester transvaginal ultrasound examination; congenital heart disease developed later. Two cases of hypoplastic left heart were diagnosed prenatally at the mid-trimester sonographic examination. The pregnancies were terminated. In the third case, a supravalvular pulmonary stenosis was discovered on the second day of life. Further investigations demonstrated a mutation on the elastin locus, thus confirming the diagnosis of Williams-Beuren syndrome. The role of nuchal translucency as a risk marker for congenital heart disease is discussed.

Topics: Cardiomegaly; Elastin; Female; Fetal Proteins; Humans; Karyotyping; Mutation; Neck; Pregnancy; Pregnancy Trimester, First; Ultrasonography, Prenatal; Williams Syndrome

A mouse platelet-derived growth factor A chain (PDGF-A) null allele is shown to be homozygous lethal, with two distinct restriction points, one prenatally before E10 and one postnatally. Postnatally surviving PDGF-A-deficient mice develop lung emphysema secondary to the failure of alveolar septation. This is apparently caused by the loss of alveolar myofibroblasts and associated elastin fiber deposits. PDGF alpha receptor-positive cells in the lung having the location of putative alveolar myofibroblast progenitors were specifically absent in PDGF-A null mutants. We conclude that PDGF-A is crucial for alveolar myofibroblast ontogeny. We have previously shown that PDGF-B is required in the ontogeny of kidney mesangial cells. The PDGFs therefore appear to regulate the generation of specific populations of myofibroblasts during mammalian development. The two PDGF null phenotypes also reveal analogous morphogenetic functions for myofibroblast-type cells in lung and kidney organogenesis.

Topics: Actins; Animals; Cardiomegaly; Chimera; Crosses, Genetic; Elastin; Fibroblasts; Gene Targeting; Lung; Mice; Mice, Mutant Strains; Muscle, Smooth; Phenotype; Platelet-Derived Growth Factor; Pulmonary Alveoli; Pulmonary Emphysema; Receptor, Platelet-Derived Growth Factor alpha; Receptors, Platelet-Derived Growth Factor; RNA, Messenger; Signal Transduction

The progression of structural changes in the pulmonary arterial bed were followed in a model of chronic pulmonary hypertension. Chronically instrumented awake sheep received continuous air embolization for 0 (controls), 1, 4, 8, or 12 days (n = 5-6/group). After the period of embolization, the lungs were removed, the pulmonary arteries were distended with barium-gelatin, and the lungs were fixed via the airways with formal-saline. Quantitative techniques were applied to sections from random blocks from the lungs of each animal. One day of embolization resulted in granulocyte sequestration in the lung interstitium and in small vessels; additionally, intraalveolar and perivascular edema was present. By 4 days, increased medial thickness, appearance of muscle in smaller arteries than normal (e.g., muscular arteries at alveolar duct level: control = 1.2 +/- 1.2%; day 4 = 22.7 +/- 7.7) and reduction in number of barium-filled intraacinar arteries was found. The arterial changes progressed in severity to day 8 and were similar at day 12. Since arterial remodelling involves increased elastin deposition, the concentration of elastin peptides was measured in lung lymph. Increased flux of elastin peptides was apparent from day 2 of embolization and continued to increase to a level 20 x baseline by day 12 (baseline 351 +/- 86 micrograms/15 min; day 12 = 6338 +/- 2999). Comparison of the onset of the structural changes with previous findings shows that the arterial remodelling parallels the onset of sustained pulmonary hypertension. The increase in lung-lymph elastin peptides by day 2 provides evidence that vascular remodelling is initiated before day 4 of embolization. The early sequestration of granulocytes and appearance of edema suggest that these may be part of the trigger to the development of the structural changes.

Topics: Angiography; Animals; Biopsy; Blood Vessels; Cardiomegaly; Chronic Disease; Elastin; Embolism, Air; Hypertension, Pulmonary; Lung; Osmolar Concentration; Peptides; Pulmonary Circulation; Sheep

Previously in rats injected with the toxin monocrotaline and administered SC-39026, a serine elastase inhibitor, pulmonary hypertension was decreased in association with reduced muscularization of peripheral pulmonary arteries. To determine whether inhibition of elastolytic activity might prevent this vascular change in other conditions producing pulmonary hypertension, we administered SC-39026 to rats during a 10-day exposure to chronic hypobaric hypoxia. We also measured elastolytic activity in the central pulmonary arteries of rats using [3H]elastin substrate and determined whether there was an increase in activity either as early as 2 days or at completion of the hypoxic exposure, which could be inhibited by SC-39026. to further determine whether the mechanism of muscularization of peripheral arteries is modulated by degradation of elastin or other elastase-susceptible extracellular matrix proteins, we assessed desmosine excretion and ultrastructural alterations in elastin as well as in type IV collagen, fibronectin, and laminin. SC-39026 reduced the number of muscularized arteries and the level of pulmonary arterial pressure during exposure to chronic hypoxia. Elastolytic activity was fourfold higher in central pulmonary arteries 2 days after hypoxia when compared with values in control vessels, and the activity was inhibited by SC-39026. In small peripheral pulmonary arteries there were no significant changes with hypoxia reflected in desmosines or in the immunocytochemistry of elastase-susceptible glycoproteins, with the exception of decreased laminin. This feature was not inhibited by SC-39026. To further assess whether the protective effect of SC-39026 was related to its inhibition of elastase, an extended study was carried out using a different elastase inhibitor, alpha 1-proteinase inhibitor. An even greater reduction in hypoxia-induced pulmonary hypertension and vascular changes was observed with this elastase inhibitor and the latter included medial hypertrophy.

Topics: alpha 1-Antitrypsin; Animals; Cardiomegaly; Chlorobenzoates; Collagen; Elastic Tissue; Elastin; Fibronectins; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Immunohistochemistry; Laminin; Male; Microscopy, Electron; Pancreatic Elastase; Pulmonary Artery; Rats; Rats, Inbred Strains

Collagen content, the ratio of collagen types I and III and elastin content were measured in 5-6- and 10-12-week-old rabbits with and without right-ventricular pressure overload. Significant and equivalent hypertrophy occurred in both age groups. A 2-day pressure overload caused a fall in collagen concentration below control levels in right-ventricular tissue from the older animals, but no change in the younger ones. A 2-week pressure overload in the older animals resulted in a rise in collagen concentration, a decreased ratio of type III to type I plus III [III/(I + III)] collagens, a fall in desmosine concentration and a fall in the desmosine/hydroxyproline ratio in the right ventricle. None of these changes occurred in the younger age group. We hypothesize that the changes in connective-tissue proteins after overload in the older group may contribute to previously observed changes in mechanical performance. The divergent connective-tissue responses in the two groups suggest the importance of age in determining outcome, as well as the possibility of separate regulatory mechanisms for contractile and for architectural elements of the heart.

Topics: Animals; Blood Pressure; Cardiomegaly; Collagen; Connective Tissue; Desmosine; Elastin; Myocardium; Rabbits

Vascular structural changes were studied during the development of two-kidney one-clip renal hypertension. The weight of the arteries and the concentration and total amount of ribonucleic acid, deoxyribonucleic acid, alkali-soluble proteins, collagen and elastin of the vascular wall were measured. Tritiated thymidine uptake was also determined 15 and 30 days after clipping. Hypertension developed in 58% of the animals while the rest remained normotensive. A significant increase in artery weight and in the total amount of nucleic acids and proteins was found in hypertensive rats. The uptake of 3H thymidine by the arteries of hypertensive rats was significantly increased 15 days after clipping. This increment showed a significant correlation with blood pressure levels. Present data seem to indicate that the increase in vessel wall dimensions observed is partly due to an increase in the number of smooth muscle cells during the acute phase; this alteration appears to be mainly due to the rise in blood pressure.

Topics: Animals; Blood Pressure; Cardiomegaly; Collagen; Disease Models, Animal; DNA; Elastin; Hyperplasia; Hypertension, Renal; Hypertension, Renovascular; Male; Muscle, Smooth, Vascular; Myocardium; Rats; Rats, Inbred Strains; RNA; Thymidine

Adding 900 p.p.m. silver (as silver nitrate) to a practical diet for chicks significantly depressed growth, increased wet and dry heart weight to body weight ratios and markedly increased mortality during a four-week experimental period. Blood packed cell volume was not affected. Supplementing the diet containing silver with 50 p.p.m. copper prevented cardiac enlargement and mortality, but only partially corrected the growth depression. Glycogen content of the heart was not affected, but aortic elastin content was significantly reduced by silver and restored to normal by supplemental copper. Dietary silver significantly reduced the copper content of blood, spleen, brain, liver, but except for the brain, the level of copper in these tissues was restored to normal by dietary copper supplementation. No significant differences in copper content of kidney tissue were observed among the treatment. Copper content of the excreta was not significantly increased by adding dietary silver, but was greatly increased by adding 50 p.p.m copper to the diet containing silver.

Topics: Administration, Oral; Animals; Aorta; Brain; Cardiomegaly; Chickens; Copper; Diet; Elastin; Glycogen; Kidney; Liver; Myocardium; Poultry Diseases; Silver; Spleen