This series of experiments will investigate the effects of an OMEGA-3 fatty acid eicosapentanoic acid (EPA), on graft and native vessel arteriosclerosis in well-defined models at the biochemical, cellular and intact animal levels. Major areas of investigation will be focused on alterations in lipoprotein metabolism, lipoprotein-macrophage interactions, characterization of immunoregulatory effects of EPA in vitro and in vivo, and assessment of the efficacy of EPA treatment in 4 independent models of experimental arteriosclerosis (viz., subendothelial myointimal cell proliferation). The objectives are to define the therapeutic potential of OMEGA-3 fish oils in cardiovascular disease and support these clinical implications with a more solid understanding of the mechanics of action involved. These investigations have direct clinical relevance to patients with solid organ vascular autographs and allografts, native arteriosclerosis, and hyperlipidemic disorders.
The specific aims are divided into 6 complementary projects to study the effects of EPA on: 1) Graft arterioscierosis, lipoprotein metabolism, lipoprotein-macrophage interaction and prostanoid metabolism in a canine veno-arterial AUTOGRAPH model. 2) Graft arteriosclerosis in a canine veno-arterial ALLOGRAFT model. 3) Graft arteriosclerosis and rejection in a rat heterotopic cardiac ALLOGRAFT model. 4) Immunocompetence in rats (humoral and cellular components) using in vivo and in vitro methods. 5) Murine and canine macrophage function, including the effects of EPA enrichment of lipoproteins on macrophage lipoprotein interactions. 6) Native vessel arteriosclerosis in SEA Japanese Quail. A multidisciplinary approach will be used to achieve these goals. The involvement of surgical (Cardiovascular), basic physiologic, immunologic (Transplantation), pathologic, and metabolic laboratories and their facilities at Stanford University will provide the most economic and complete scientific investigation.
