UP-REGULATION OF FIBRONECTIN SYNTHESIS BY INTERLEUKIN-1-BETA IN CORONARY-ARTERY SMOOTH-MUSCLE CELLS IS ASSOCIATED WITH THE DEVELOPMENT OF THE POST-CARDIAC TRANSPLANT ARTERIOPATHY IN PIGLETS

We previously described in piglets after heterotopic cardiac transplantation the early development of a coronary arteriopathy characterized by increased immunostaining for fibronectin and interleukin-1beta (IL-1beta) in the vessel wall. The objective of this study was to culture smooth muscle cells from donor and host coronary arteries in these piglets to determine whether donor cells produce more fibronectin than host cells as judged by increased protein and mRNA levels, and whether IL-1beta may be regulating this increase by an autocrine mechanism involving increased production of the cytokine. We documented increased donor coronary artery smooth muscle cell fibronectin protein synthesis and mRNA compared to host. By using neutralizing antibodies to IL-1beta, fibronectin protein synthesis and mRNA levels were reduced in donor cells to the levels observed in the host cells and a similar reduction in synthesis was observed with the IL-1 receptor antagonist. Immunoprecipitation of newly synthesized IL-1beta revealed increased endogenous levels in donor compared to host cells. We therefore suggest in the coronary arteriopathy a pathophysiologic mechanism whereby IL-1beta-mediated increased fibronectin synthesis may promote lymphocyte trapping and migration of medial smooth muscle cells leading to progressive intimal thickening associated with the post-cardiac transplant coronary arteriopathy.