elastin and Coronary-Disease

The extracellular matrix provides a structural framework essential for the functional properties of vessel walls. The three dimensional organization of the extracellular matrix molecules--elastin, collagens, proteoglycans and structural glycoproteins--synthesized during fetal development--is optimal for these functions. Early in life, the vessel wall is subjected to injury: lipid deposition, hypoxia, enzyme secretion and reactive oxygen species production during inflammatory processes, and the extracellular matrix molecules are hydrolyzed by proteases--matrix metalloproteinases, leukocyte elastase, etc. In uninjured arteries and veins, some proteases are constitutively expressed, but through the control of their activation and/or their inhibition by inhibitors, these proteases have a very low activity. During the occurrence of vascular pathologies--atherosclerosis, hypertension, varicosis, restenosis, etc.--the balance between proteases and their inhibitors is temporally destroyed through the induction of matrix metalloproteinase gene expression or the secretion of enzymes by inflammatory cells. Smooth muscle cells, the most numerous cells in vascular walls, have a high ability to respond to injury through their ability to synthesize extracellular matrix molecules and protease inhibitors. However, the three dimensional organization of the newly synthesized extracellular matrix is never functionally optimal. In some other pathologies--aneurysm--the injury overcomes the responsive capacity of smooth muscle cells and the quantity of extracellular matrix decreases. In conclusion, care should be taken to maintain the vascular extracellular matrix reserve and any therapeutic manipulation of the protease/inhibitor balance must be perfectly controlled, because an accumulation of abnormal extracellular matrix may have unforeseen adverse effects.

Topics: Aneurysm; Animals; Blood Vessels; Collagen; Coronary Disease; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Hypertension; Varicose Veins

Topics: Aging; Animals; Aorta; Arteries; Arteriosclerosis; Cholesterol; Collagen; Coronary Disease; Coronary Vessels; Elastin; Endothelium; Glucose; Glycosaminoglycans; Humans; Lipoproteins; Lipoproteins, VLDL; Phagocytosis; Platelet Adhesiveness; Vasa Vasorum

Coronary artery angioplasty triggers healing that causes constrictive remodeling. Because collagen accumulation correlates with constrictive remodeling and aldosterone has been implicated in collagen accumulation, we examined how aldosterone and the mineralocorticoid receptor antagonists spironolactone and eplerenone affect remodeling and collagen in porcine coronary and iliac arteries after angioplasty.. Twenty-four pigs were allocated into 4 treatment groups: oral eplerenone (100 mg/d), oral spironolactone (200 mg/d), subcutaneous aldosterone (400 microgram/d), or no treatment. Twenty-eight days after angioplasty of the coronary arteries, eplerenone increased total vessel area by 30% (P<0.05) and luminal area by nearly 60% (P<0.05) compared with the no-treatment group, without affecting neointima size. These effects were accompanied by a 65% reduction in neointimal and medial collagen density (both P<0.05). Spironolactone was less effective, and aldosterone tended to exert opposite effects on coronary artery structure after angioplasty. These effects were not observed in angioplastied iliac arteries.. Eplerenone attenuates constrictive remodeling after coronary artery angioplasty by mechanisms involving reduction in collagen accumulation, which thus appears to be an important contributor to constrictive remodeling of angioplastied coronary arteries.

Topics: Aldosterone; Angioplasty, Balloon; Animals; Collagen; Constriction, Pathologic; Coronary Disease; Coronary Vessels; Elastin; Eplerenone; Iliac Artery; Male; Mineralocorticoid Receptor Antagonists; Spironolactone; Swine; Swine, Miniature; Tunica Intima

Restenotic neointimal lesions, a major limitation to coronary angioplasty, develop in response to diverse signals and depend on three properties of activated arterial smooth muscle cells (SMCs): proliferation, migration, and abnormal production of extracellular matrix. Most of the pharmacologic approaches targeting specific pathogenic factors facilitating development of restenosis have failed in clinical trials. Our results indicate that the polysulfonated naphthylurea suramin, a "non-specific drug" that interferes with multiple cellular proteins, inhibits neointimal formation in rabbit iliac arteries after balloon-catheter injury administered throughout the critical period of several weeks after the procedure. In vitro studies aimed at dissecting the mechanism(s) underlying the suramin-dependent effect demonstrated that, in addition to an inhibitory effect on SMC proliferation, suramin inhibited fibronectin and elastin deposition and the migration of SMCs through elastin membranes and into scratch gaps of monolayer cultures. We also demonstrated that suramin causes cell-surface accumulation of the elastin binding protein, a receptor that not only anchors SMCs to the extracellular matrix, but also inhibits SMC response to interleukin-1beta (IL-1beta). We conclude that suramin acts as a multitarget inhibitor of SMC activation and has a therapeutic potential as an agent that may attenuate arterial restenosis after angioplasty.

Topics: Angioplasty, Balloon; Animals; Antineoplastic Agents; Cell Culture Techniques; Cell Division; Cell Movement; Coronary Disease; DNA; Elastin; Fibronectins; Iliac Artery; Immunohistochemistry; Interleukin-1; Male; Muscle, Smooth, Vascular; Nucleotide Mapping; Protein Binding; Rabbits; Receptors, Cell Surface; Suramin; Tunica Intima

Formation of the atherosclerotic intima must involve altered metabolism of the elastin-rich arterial extracellular matrix. Proteases potentially involved in these processes remain unclear. This study examined the expression of the potent elastases cathepsins S and K in human atheroma. Normal arteries contained little or no cathepsin K or S. In contrast, macrophages in atheroma contained abundant immunoreactive cathepsins K and S. Intimal smooth muscle cells (SMC), especially cells appearing to traverse the internal elastic laminae, also contained these enzymes. Extracts of atheromatous tissues had approximately twofold greater elastase-specific activity than extracts of uninvolved arteries, mostly due to cysteine proteases. Cultured human SMC displayed no immunoreactive cathepsins K and S and exhibited little or no elastolytic activity when incubated with insoluble elastin. SMC stimulated with the atheroma-associated cytokines IL-1beta or IFN-gamma secreted active cathepsin S and degraded substantial insoluble elastin (15-20 microg/10(6) cells/24 h). A selective inhibitor of cathepsin S blocked > 80% of this elastolytic activity. The presence of cathepsins K and S at sites of vascular matrix remodeling and the ability of SMC and macrophages to use these enzymes to degrade elastin supports a role for elastolytic cathepsins in vessel wall remodeling and identifies novel therapeutic targets in regulating plaque stability.

Topics: Arteriosclerosis; Carotid Stenosis; Cathepsin K; Cathepsins; Cells, Cultured; Coronary Disease; Elastin; Enzyme Induction; Humans; Interferon-gamma; Muscle, Smooth, Vascular; RNA, Messenger; Tunica Intima

To understand the balance of proteinase antiproteinase activity and the production of extracellular matrix (ECM) at the site of arterial injury, we analyzed the composition of ECM and proteinase activity in normal internal mammary arteries, tissue samples obtained from atherosclerotic coronary lesions and restenotic lesions obtained during directional coronary atherectomy. Histologically and biochemically, collagen and proteoglycans increased, and elastin decreased in samples from restenotic lesions when compared to samples taken from patients undergoing their first revascularization (de novo). In contrast, cellularity was increased in samples obtained from de novo patients as compared to samples obtained from restenotic lesions. Intrinsic activity of matrix metalloproteinases (MMPs) was measured by using zymography and scanning all the lytic bands in zymographic gel. In these gels, identical amounts of total protein were loaded in each lane. MMP activity was determined as % of the total (latent and active) MMPs after trypsin activation (100%) in the normal artery. Intrinsic MMP activity was reduced to 6% +/- 1% in atherosclerotic lesions and 1% +/- 1% in restenotic lesions, when compared to activity found in normal (10% +/- 3%) arteries. Based on solubilization of fluorescein-conjugated elastin by the extracts, the MMP-mediated elastinolytic activity was 0.2 +/- 0.1, 8.8 +/- 1.5, and 24.0 +/- 3 nmol/min/mg in restenotic, native atherosclerotic and normal tissue, respectively. The results suggested that, in arterial tissue from patients with angiographic restenosis, there is an increased production of ECM collagen and a decrease in MMP activity compared to both normal artery and atherosclerotic samples from de novo patients undergoing an initial revascularization procedure of a significant coronary artery lesion.

Topics: Angioplasty, Balloon; Arteriosclerosis; Atherectomy; Collagen; Coloring Agents; Coronary Disease; Coronary Vessels; Elastin; Extracellular Matrix Proteins; Glycoproteins; Humans; Internal Mammary-Coronary Artery Anastomosis; Metalloendopeptidases; Models, Biological; Proteoglycans; Recurrence; Tissue Inhibitor of Metalloproteinases; Wound Healing

In experimental piglets after heterotopic heart transplant, we observed an immune/inflammatory response in the coronary arteries with increased expression of interleukin-1 beta and accumulation of fibronectin and smooth muscle cells in the subendothelium (N. Clausell, S. Molossi, M. Rabinovitch, Am J Pathol 1993, 142, 1772-1786). Proteolytic enzymes including elastases regulate cytokine activity and are associated with the development of neointimal proliferation. We now report ultrastructural evidence of elastolytic activity in the donor compared to host coronary arteries judged by a fivefold increase in the breaks in the internal elastic lamina, (P < 0.01) correlating with a 10-fold increase in elastase activity per mg tissue (P < 0.01). The enzyme activity is serine elastase, i.e., inhibited by phenylmethyl sulfonyl fluoride, and elafin but not EDTA. Using a novel strategy that greatly increases the activity extractable from the tissue, we resolved the enzyme on an elastin substrate gel as a protein of approximately 23 kd. Ours is the first report and characterization of increased elastase activity associated with the development of the post-cardiac transplant coronary arteriopathy. The source may be inflammatory or smooth muscle cells, and elastase may play a pathophysiological role in neointimal proliferation by activating cytokines and growth factors and by release of chemotactic peptides.

Topics: Animals; Coronary Disease; Elastin; Heart Transplantation; Microscopy, Electron; Pancreatic Elastase; Postoperative Complications; Serine; Swine

The degradation of elastin during various pathological processes such as emphysema or arteriosclerosis was demonstrated by several investigators. In the present work, we adapted an ELISA technique for the determination of elastin peptide (EP) levels in human sera and plasma, in healthy and arteriosclerotic subjects. This test makes use of human aorta elastin hydrolyzed by a chemical procedure (kappa-elastin) instead of EP produced by pancreatic or leukocyte elastase. Polyclonal antibodies to this antigen were obtained in rabbits. The indirect ELISA procedure is sensitive, specific and reproducible. No correlation could be demonstrated between EP level and anti-EP antibody concentration of IgG or IgM types determined in the same serum samples. These antibodies did not interfere with EP determinations. EP concentration did not change with age in control subjects. In obliterative arteriosclerosis of the legs and in type IIb hyperlipoproteinemia, EP levels showed a marked increase, while in hypertension, ischemic heart disease and diabetes mellitus, the increase was moderate. In stroke, only slight changes were observed. In type IV hyperlipoproteinemia, EP levels were lower than in controls.

Topics: Adult; Age Factors; Aged; Aorta; Arteriosclerosis; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus; Elastin; Enzyme-Linked Immunosorbent Assay; Humans; Hydrolysis; Hyperlipoproteinemias; Hypertension; Immunoglobulin G; Immunoglobulin M; Leg; Middle Aged; Peptides; Sensitivity and Specificity

We adapted a highly sensitive and reproducible ELISA technique for the determination of anti-elastin peptide antibodies of IgG type AEAb-IgG) and IgM type AEAb-IgM) in human sera. The determination was performed in the sera of 265 normal and diseased persons. The pathologies studied included obliterative arteriosclerosis of the legs, ischemic heart disease, stroke, diabetes mellitus, type IIb and IV hyperlipoproteinemia and hypertension. No clearcut correlation could be found between AEAb and age. In contrast, in arteriosclerotic patients and especially in obliterative arteriosclerosis of the legs and ischemic heart disease, the concentration of AEAb-IgG was significantly increased. The AEAb-IgM showed no change in the studied diseases. Both types of AEAb were decreased in type IV hyperlipoproteinemia. Anti-elastin antibodies may be involved in the pathomechanisms of the above diseases and the determination of antibody concentrations may be of some help in obliterative arteriosclerotic diseases.

Topics: Adult; Aged; Antibodies; Arteriosclerosis; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hyperlipoproteinemia Type II; Hyperlipoproteinemia Type IV; Male; Middle Aged; Peptides

In order to further investigate the role of the immune system in the arteriosclerotic process, we investigated the anti-elastin peptide antibodies (AEAb) of the IgG and IgM types by DOT immunobinding assay in the sera of patients suffering from various arteriosclerotic diseases. In total 232 control and pathological sera were studied. In obliterative arteriosclerosis of the legs 90%, ischemic heart disease 67% and hypertension 60% of sera were positive for AEAb of the IgG type independent of age. In the case of diabetes mellitus, however, the duration of the disease was determinant. In rheumatoid arthritis, the results were negative. No clear-cut positivity could be demonstrated in stroke patients either. These results indicate that AEAb can be detected in some diseases and DOT appears to be an appropriate method for the AEAb screening in various diseases.

Topics: Adult; Age Factors; Aged; Arteriosclerosis; Arthritis, Rheumatoid; Coronary Disease; Diabetes Mellitus; Elastin; Female; Humans; Hypertension; Immunoglobulin G; Immunoglobulin M; Immunosorbent Techniques; Male; Middle Aged; Peptide Fragments

Electron-microscopic examination of spontaneously occurring coronary arterial lesions in adult spawning steelhead trout showed them to be subendothelial accumulations of modified smooth muscle cells covered by an intact endothelium. Some of the cells in the nodules appeared highly vacuolated and seemed to be associated with varying amounts of collagen and elastin. The internal elastic lamina was often doubled with smooth muscle cells between the layers. The thickness of the internal elastica was altered and, in some lesions, penetrated by smooth muscle cells. In the smallest lesions, smooth muscle cells appeared to be penetrating the internal elastic lamina and were usually close to a highly vacuolated intimal endothelial cell. The underlying medial layer frequently exhibited altered orientation of the cells, with the frequent appearance of increased collagen and amorphous extracellular material. No lipid was present in any lesion. Although vacuolation of endothelial cells suggested some alteration in endothelial cells, at least in developed lesions, no evidence of endothelial denudation over lesions was observed.

Topics: Animals; Arteries; Blood Platelets; Collagen; Coronary Disease; Coronary Vessels; Elastin; Endothelium; Leukocytes; Muscle, Smooth; Time Factors; Trout

Topics: Animals; Aorta; Arteries; Arteriosclerosis; Aspirin; Calcium; Cholesterol; Cholesterol, Dietary; Collagen; Coronary Disease; Coronary Vessels; Diet, Atherogenic; Dipyridamole; Elastin; Haplorhini; Lipoproteins, LDL; Macaca fascicularis

Mitral valve, coronary arteries, cartilage, and liver were studied by light and electron microscopy in a 15 year old boy with Morquio's syndrome, a genetic mucopolysaccharidosis, in which a deficiency of lysosomal hexosamine sulfatase is associated with accumulations of keratan sulfate in various organs. Coronary artery intimal sclerosis was a prominent feature of this disorder. Ultrastructural examination revealed numerous intimal smooth muscle cells containing storage vacuoles consistent with lysosomes. This was associated with marked interstitial deposition of collagen, elastin, and basement membrane material. Recent studies of human and experimental atherosclerosis have demonstrated the accumulation of cholesterol within vascular smooth muscle cell lysosomes. Intralysosomal accumulation of substrates other than cholesterol is also associated with vascular intimal sclerosis in genetic lysosomal disorders such as Fabry's disease and Hurler's syndrome. Lysosomal storage of undegraded substrate may be an important pathogenetic mechanism in the development of sclerotic vascular lesions.

Topics: Adolescent; Arteriosclerosis; Basement Membrane; Collagen; Coronary Disease; Coronary Vessels; Elastin; Humans; Liver; Male; Microscopy, Electron; Mucopolysaccharidosis IV; Muscle, Smooth; Vacuoles

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Collagen; Coronary Disease; Coronary Vessels; Diet, Atherogenic; Disease Models, Animal; Eggs; Elastin; Endothelium; Female; Femoral Artery; Hypercholesterolemia; Iliac Artery; Inclusion Bodies; Male; Marsupialia; Meat; Microscopy, Electron

Topics: Animals; Arteries; Arteriosclerosis; Blood Proteins; Cells, Cultured; Cholesterol; Coronary Disease; Elastic Tissue; Elasticity; Elastin; Glycosaminoglycans; Haplorhini; Lipoproteins, HDL; Lipoproteins, LDL; Macaca; Microscopy, Electron; Muscle, Smooth

Topics: Adolescent; Adult; Age Factors; Aged; Aorta; Arteries; Arteriosclerosis; Black People; Calcium; Cerebral Arteries; Cerebrovascular Disorders; Child; Child, Preschool; Cholesterol; Collagen; Coronary Disease; Coronary Vessels; Elastin; Female; Hexosamines; Histocytochemistry; Humans; Infant; Infant, Newborn; Lipids; Male; Middle Aged; Phospholipids; Sex Factors; South Africa; Thrombosis; Triglycerides; White People

Topics: Angiography; Animals; Arteries; Chronic Disease; Collagen; Collateral Circulation; Coronary Disease; Coronary Vessels; Dogs; Elastin; Female; Glycosaminoglycans; Histocytochemistry; Male; Mitosis; Regeneration

Topics: Aging; Arteriosclerosis; Carbon; Coronary Disease; Coronary Vessels; Elastin; Glycosaminoglycans; Staining and Labeling

Topics: Aortic Valve; Coronary Disease; Death, Sudden; Elastin; Embolism; Heart Neoplasms; Heart Valve Diseases; Hemosiderin; Humans; Mucins; Myxoma; Pathology; Polyps

Topics: Animals; Aorta, Thoracic; Copper; Coronary Disease; Coronary Vessels; Deficiency Diseases; Elastic Tissue; Elastin; Iron; Pathology; Proteins; Research; Swine