Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits afer heterotopic cardiac transplantation.
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.
Cowan
B
B
Division of Cardiovascular Research, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Baron
O
O
Crack
J
J
Coulber
C
C
Wilson
G J
GJ
Rabinovitch
M
M
D000818:Animals; D002455:Cell Division; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology* / Q000637:transplantation*; D005353:Fibronectins / Q000032:analysis; D006321:Heart / Q000187:drug effects; D016027:Heart Transplantation / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D009336:Necrosis; D010196:Pancreatic Elastase / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000494:pharmacology*; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D016042:Transplantation, Heterotopic; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D005353:Fibronectins; D018809:Proliferating Cell Nuclear Antigen; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D010196:Pancreatic Elastase