In vivo collagen turnover following experimental balloon angioplasty injury and the role of matrix metalloproteinases.

Extracellular matrix formation is the major component of the restenosis lesion that develops after balloon angioplasty. Although ex vivo studies have shown that the synthesis of collagen is stimulated early after balloon angioplasty, there is a delay in accumulation in the vessel wall. The objectives of this study were to assess collagen turnover and its possible regulation by matrix metalloproteinases (MMPs) in a double-injury iliac artery rabbit model of restenosis. Rabbits were killed at four time points (immediately and at 1, 4, and 12 weeks) after balloon angioplasty. In vivo collagen synthesis and collagen degradation were measured after a 24-hour incubation with [14C]proline. Arterial extracts were also run on gelatin zymograms to determine MMP (gelatinase) activity. Collagen turnover studies were repeated in a group of 1-week postangioplasty rabbits that were treated with daily subcutaneous injections of either a nonspecific MMP inhibitor, GM6001 (100 mg/kg per day), or placebo. Collagen synthesis and degradation showed similar temporal profiles, with significant increases in the balloon-injured iliac arteries compared with control nondilated contralateral iliac arteries immediately after angioplasty and at 1 and 4 weeks. Peak collagen synthesis and degradation occurred at 1 week and were increased (approximately four and three times control values, respectively). Gelatin zymography was consistent with the biochemical data by showing an increase of a 72-kD gelatinase (MMP-2) in the balloon-injured side immediately after the second injury, peaking at 1 week, and still detectable at 4 and 12 weeks (although at lower levels). In balloon-injured arteries, the MMP inhibitor reduced both collagen synthesis and degradation. Overall, at 1 week after balloon angioplasty, GM6001 resulted in a 33% reduction in collagen content in balloon-injured arteries compared with placebo (750 +/- 143 to 500 +/- 78 micrograms hydroxyproline per segment, P < .004), which was associated with a nonsignificant 25% reduction in intimal area. Our data suggest that degradation of newly synthesized collagen is an important mechanism regulating collagen accumulation and that MMPs have an integral role in collagen turnover after balloon angioplasty.

[1]  R. Ikegawa,et al.  Phosphoramidon inhibits the generation of endothelin‐1 from exogenously applied big endothelin‐1 in cultured vascular endothelial cells and smooth muscle cells , 1991, FEBS letters.

[2]  F. Yamasawa,et al.  Age-Dependent Changes of Collagen and Elastin Content in Human Aorta and Pulmonary Artery , 1984, Angiology.

[3]  R. Bienkowski.  Intracellular degradation of newly synthesized collagen. , 1984, Revisiones sobre biologia celular : RBC.

[4]  J. McEwan,et al.  Matrix metalloproteinases and cardiovascular disease. , 1995, Circulation research.

[5]  L. Matrisian.  The matrix‐degrading metalloproteinases , 1992, Journal of neuro-oncology.

[6]  A. Clowes,et al.  Induction of Tissue Inhibitor of Metalloproteinase‐2 in Injured Rat Artery a , 1994, Annals of the New York Academy of Sciences.

[7]  R. Ikegawa,et al.  Conversion of big endothelin-1 to endothelin-1 by two-types of metalloproteinases of cultured porcine vascular smooth muscle cells. , 1991, Biochemical and biophysical research communications.

[8]  G. Laurent.  Rates of collagen synthesis in lung, skin and muscle obtained in vivo by a simplified method using [3H]proline. , 1982, The Biochemical journal.

[9]  M. Ledvina,et al.  Collagen, elastin and desmosines in three layers of bovine aortas of different ages , 1979, Experimental Gerontology.

[10]  G. Laurent,et al.  Dynamic state of collagen: pathways of collagen degradation in vivo and their possible role in regulation of collagen mass. , 1987, The American journal of physiology.

[11]  P. Armstrong,et al.  Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis. , 1994, Circulation research.

[12]  R. Bast,et al.  Regulation of tumour necrosis factor-α processing by a metalloproteinase inhibitor , 1994, Nature.

[13]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[14]  K. Kivirikko,et al.  Modifications of a specific assay for hydroxyproline in urine. , 1967, Analytical biochemistry.

[15]  D. Belin,et al.  Smooth muscle cells express urokinase during mitogenesis and tissue-type plasminogen activator during migration in injured rat carotid artery. , 1990, Circulation research.

[16]  R. Diegelmann,et al.  Use of a mixture of proteinase-free collagenases for the specific assay of radioactive collagen in the presence of other proteins. , 1971, Biochemistry.

[17]  D. Laskin,et al.  Chemotactic Activity of Collagen‐Like Polypeptides for Human Peripheral Blood Neutrophils , 1986, Journal of leukocyte biology.

[18]  Z. Werb,et al.  Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. , 1986, The Journal of biological chemistry.

[19]  R. Palmiter,et al.  Rabbit procollagenase synthesized and secreted by a high-yield mammalian expression vector requires stromelysin (matrix metalloproteinase-3) for maximal activation. , 1990, The Journal of biological chemistry.

[20]  R. Kandel,et al.  Inverse correlation between tyrosine phosphorylation and collagenase production in chondrocytes. , 1990, The Biochemical journal.

[21]  A. Samarel,et al.  Regulation of procollagen metabolism in the pressure-overloaded rat heart. , 1993, The Journal of clinical investigation.

[22]  James P. Quigley,et al.  Matrix Metalloproteinase-2 Is an Interstitial Collagenase , 1995, The Journal of Biological Chemistry.

[23]  A. Mantovani,et al.  Cytokines as communication signals between leukocytes and endothelial cells. , 1989, Immunology today.

[24]  A. Clowes,et al.  Heparin inhibits collagenase gene expression mediated by phorbol ester-responsive element in primate arterial smooth muscle cells. , 1992, Circulation research.

[25]  M. Rabinovitch,et al.  Inhibition of elastolysis by SC-37698 reduces development and progression of monocrotaline pulmonary hypertension. , 1991, The American journal of physiology.

[26]  P. Libby,et al.  Atherogenic diets enhance endotoxin-stimulated interleukin-1 and tumor necrosis factor gene expression in rabbit aortae. , 1992, The Journal of nutrition.

[27]  A. Albini,et al.  Collagenolytic cleavage products of collagen type I as chemoattractants for human dermal fibroblasts. , 1985, European journal of cell biology.

[28]  E. Lakatta,et al.  Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation. , 1994, Circulation research.

[29]  M J Banda,et al.  Secretion of metalloproteinases by stimulated capillary endothelial cells. I. Production of procollagenase and prostromelysin exceeds expression of proteolytic activity. , 1986, The Journal of biological chemistry.

[30]  A. H. Drummond,et al.  Processing of tumour necrosis factor-α precursor by metalloproteinases , 1994, Nature.

[31]  C. Vater,et al.  Preparation of a monospecific antibody to purified rabbit synovial fibroblast collagenase. , 1981, Collagen and related research.

[32]  M. Gerhart,et al.  Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing , 1994, Nature.

[33]  A. Samarel,et al.  Histomorphometric and biochemical correlates of arterial procollagen gene expression during vascular repair after experimental angioplasty. , 1995, Circulation.

[34]  P. Serruys,et al.  Directional atherectomy for treatment of restenosis within coronary stents: clinical, angiographic and histologic results. , 1992, Journal of the American College of Cardiology.

[35]  P. Libby,et al.  Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. , 1994, The Journal of clinical investigation.

[36]  R. Mayne.  Collagenous proteins of blood vessels. , 1986, Arteriosclerosis.

[37]  J. Kishi,et al.  Synthesis of latent collagenase and collagenase inhibitor by bovine aortic medial explants and cultured medial smooth muscle cells. , 1989, Connective tissue research.

[38]  E. Nabel,et al.  Biology of the impaired endothelium. , 1991, The American journal of cardiology.

[39]  N. Blumenkrantz,et al.  Simple procedures for determination of [14C] hydroxyproline. , 1975, Analytical biochemistry.

[40]  M. Reidy,et al.  Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. , 1994, Circulation research.

[41]  P. Libby,et al.  Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. , 1994, Circulation research.

[42]  P. Libby,et al.  Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[43]  E J Topol,et al.  The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. , 1992, Journal of the American College of Cardiology.

[44]  M. Reidy,et al.  Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. , 1996, Circulation research.

[45]  J. Woessner,et al.  Matrix metalloproteinases and their inhibitors in connective tissue remodeling , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[46]  A. Newby,et al.  Involvement of extracellular-matrix-degrading metalloproteinases in rabbit aortic smooth-muscle cell proliferation. , 1992, The Biochemical journal.

[47]  Y Okada,et al.  Collagens in human atherosclerosis. Immunohistochemical analysis using collagen type-specific antibodies. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[48]  A. Gotlieb,et al.  Expression of tumour necrosis factor alpha and accumulation of fibronectin in coronary artery restenotic lesions retrieved by atherectomy. , 1995, British heart journal.

[49]  J. Malone,et al.  Recruitment of peripheral mononuclear cells by mammalian collagenase digests of type I collagen. , 1991, Matrix.