Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits afer heterotopic cardiac transplantation

J Clin Invest. 1996 Jun 1;97(11):2452-68. doi: 10.1172/JCI118692.


We have related experimentally induced post-cardiac transplant coronary arteriopathy to increased elastolytic activity, IL-1beta, fibronectin-mediated inflammatory and smooth muscle cell (SMC) migration, and SMC proliferation. Since our in vitro studies show that a serine elastase releases SMC mitogens and facilitates IL-lbeta induction of fibronectin, we hypothesized that administration in vivo of the specific serine elastase inhibitor, elafin, would decrease the post-cardiac transplant coronary arteriopathy. Cholesterol-fed rabbits underwent a heterotopic cardiac transplant without immunosuppression and received elafin (1.79 mg/kg per d continuous infusion after a 9 mg bolus, n = 6) or vehicle (n = 6). 1 wk later, hearts were harvested for morphometric, immunohistochemical, and biochemical analyses. A > 70% decrease in the total number of coronary arteries with intimal thickening in elafin-treated compared to control donor hearts (P < 0.002) was associated with reduced vascular elastolytic activity judged by fewer breaks in the internal elastic lamina (P < 0.03), less accumulation of immunoreactive fibronectin (P < 0.02), and reduced cell proliferation quantified by proliferating cell nuclear antigen (P < 0.0001). Despite myocardial lymphocytic infiltration, wet weight of elafin-treated donor hearts was reduced by 50% compared to untreated controls (P < 0.002) and associated with relative preservation of myocyte integrity, instead of extensive myocardial necrosis (P < 0.004). This protective effect correlated with decreased myocardial elastolytic activity (P < 0.0001) and inflammatory cell proliferation (P < 0.0001) and with an elafin-inhibitable elastase in lymphocytes. Serine elastase activity thus appears an important therapeutic target for post-cardiac transplant coronary arteriopathy and myocardial necrosis induced by rejection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division
  • Coronary Vessels / drug effects
  • Coronary Vessels / pathology*
  • Coronary Vessels / transplantation*
  • Fibronectins / analysis
  • Heart / drug effects
  • Heart Transplantation / pathology*
  • Humans
  • Immunohistochemistry
  • Inflammation
  • Necrosis
  • Pancreatic Elastase / analysis
  • Proliferating Cell Nuclear Antigen / analysis
  • Proteinase Inhibitory Proteins, Secretory
  • Proteins / pharmacology*
  • Rabbits
  • Recombinant Proteins / pharmacology
  • Serine Proteinase Inhibitors / pharmacology*
  • Transplantation, Heterotopic
  • Tunica Intima / drug effects
  • Tunica Intima / pathology


  • Fibronectins
  • Proliferating Cell Nuclear Antigen
  • Proteinase Inhibitory Proteins, Secretory
  • Proteins
  • Recombinant Proteins
  • Serine Proteinase Inhibitors
  • Pancreatic Elastase