Arterial Elastase Activity After Balloon Angioplasty and Effects of Elafin, an Elastase Inhibitor

Increased proteolytic activity may be a factor in intimal hyperplasia after balloon angioplasty (BA). The objectives of this study were to assess elastase activity after BA in a rabbit arterial double-injury model and the effects of elastase inhibition. Elastase activity increased immediately after BA, reached an 8-fold peak at 1 week, and declined to baseline levels by 4 weeks. Elastin zymography showed that the elastase activity was associated predominantly with a molecular mass of 25 kDa. Elastase activity was significantly inhibited in vitro by elafin and phenylmethylsulfonyl fluoride, selective inhibitors of serine elastases. A second group of animals was transfected after BA with a plasmid containing the cDNA for either elafin or a control (chloramphenicol acetyltransferase, CAT) construct by using a hemagglutinating virus of Japan–liposome transfection technique. Arterial segments were obtained at 48 hours, 1 week, and 4 weeks to assess transgene expression, arterial wall elastase activity, and intimal cross-sectional area, respectively. Elafin transgene expression was evident at 48 hours and resulted in a significant (80%) inhibition of elastase activity compared with chloramphenicol acetyltransferase–transfected arteries. There was a 43% reduction in intimal cross-sectional area in elafin-transfected arteries (0.28±0.22 versus 0.16±0.07 mm2 for CAT-transfected versus elafin-transfected arteries, respectively;P <0.05). These data suggest that an early increase in serine elastase activity after BA contributes to intimal hyperplasia. Serine elastase inhibition may be a potential therapeutic approach to inhibit intimal hyperplasia.

[1]  Y. Kaneda,et al.  Gene Transfer of the Serine Elastase Inhibitor Elafin Protects Against Vein Graft Degeneration , 2000, Circulation.

[2]  M. Rabinovitch,et al.  Suppressed smooth muscle proliferation and inflammatory cell invasion after arterial injury in elafin-overexpressing mice. , 2000, The Journal of clinical investigation.

[3]  Adrian M Heilbut,et al.  Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor , 2000, Nature Medicine.

[4]  M. Rabinovitch.  EVE and beyond, retro and prospective insights. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[5]  M. Jeune,et al.  Effect of Matrix Metalloproteinase Inhibition on Progression of Atherosclerosis and Aneurysm in LDL Receptor‐Deficient Mice Overexpressing MMP‐3, MMP‐12, and MMP‐13 and on Restenosis in Rats after Balloon Injury , 1999, Annals of the New York Academy of Sciences.

[6]  M. Rabinovitch,et al.  Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis. , 1999, The Journal of clinical investigation.

[7]  J. K. Lee,et al.  A serine elastase inhibitor reduces inflammation and fibrosis and preserves cardiac function after experimentally-induced murine myocarditis , 1998, Nature Medicine.

[8]  P. Libby,et al.  Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. , 1998, The Journal of clinical investigation.

[9]  É. Allaire,et al.  Metalloproteinase blockade by local overexpression of TIMP-1 increases elastin accumulation in rat carotid artery intima. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[10]  Y. Yoshida,et al.  Migration of Medial Smooth Muscle Cells to the Intima after Balloon Injury , 1997, Annals of the New York Academy of Sciences.

[11]  B. Strauss,et al.  In vivo collagen turnover following experimental balloon angioplasty injury and the role of matrix metalloproteinases. , 1996, Circulation research.

[12]  G. Wilson,et al.  Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits afer heterotopic cardiac transplantation. , 1996, The Journal of clinical investigation.

[13]  M. Rabinovitch,et al.  Exogenous leukocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular matrix‐bound basic fibroblast growth factor , 1996, Journal of cellular physiology.

[14]  A. Gotlieb,et al.  Increased elastin-degrading activity and neointimal formation in porcine aortic organ culture. Reduction of both features with a serine proteinase inhibitor. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[15]  J. Taipale,et al.  Human Mast Cell Chymase and Leukocyte Elastase Release Latent Transforming Growth Factor-β1 from the Extracellular Matrix of Cultured Human Epithelial and Endothelial Cells (*) , 1995, The Journal of Biological Chemistry.

[16]  M. Jordana,et al.  Regulation of secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (ESI/elafin) in human airway epithelial cells by cytokines and neutrophilic enzymes. , 1994, American journal of respiratory cell and molecular biology.

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

[18]  M. Zuker,et al.  The endogenous vascular elastase that governs development and progression of monocrotaline-induced pulmonary hypertension in rats is a novel enzyme related to the serine proteinase adipsin. , 1994, The Journal of clinical investigation.

[19]  M. Rabinovitch,et al.  Post-cardiac transplant arteriopathy in piglets is associated with fragmentation of elastin and increased activity of a serine elastase. , 1994, The American journal of pathology.

[20]  L. McCready,et al.  Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. , 1992, The American review of respiratory disease.

[21]  M. Rabinovitch,et al.  Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity. , 1991, The American journal of physiology.

[22]  E. Turley,et al.  Fibronectin, hyaluronan, and a hyaluronan binding protein contribute to increased ductus arteriosus smooth muscle cell migration. , 1991, Developmental biology.

[23]  J. Schröder,et al.  Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. , 1990, The Journal of biological chemistry.

[24]  K. Iwai,et al.  Introduction and expression of the human insulin gene in adult rat liver. , 1989, The Journal of biological chemistry.

[25]  H. Moses,et al.  Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium , 1988, The Journal of cell biology.

[26]  P. Jones,et al.  Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. , 2000, The Journal of clinical investigation.

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