Activated macrophage foam cells contribute to the pathogenesis of atherosclerosis and the onset of its acute thrombotic complications. We will test the novel hypothesis in vitro and in vivo that apolipoprotein CIII (apoCIII) promotes macrophage foam cell formation (lipid uptake) and activation (induction of atherogenic factors). ApoCIII inhibits lipoprotein clearance from plasma, leading to the higher concentrations of VLDL and LDL. While these effects may account for the association of elevated apoCIII levels with atherogenesis, clinical evidence suggests that apoCIII predicts coronary heart disease independent of the conventional lipid profile. Our preclinical findings, documented in four publications, suggest in vitro that apoCIII induces monocyte adhesion to endothelial cells, a key step in the initiation of atherosclerosis. Our preliminary studies have demonstrated that, in cultured human macrophages, apoCIII increases expression of the scavenger receptor LOX-1. Macrophage scavenger receptors mediate conversion of these phagocytes into the lipid-laden foam cells, and participate in atherogenesis. ApoCIII also induced macrophage expression of various atherogenic molecules in vitro. The present study will explore in vitro the effects of apoCIII on foam cell formation and activation of macrophages and examine whether apoCIII accelerates atherogenesis in mouse models to determine the reality in vivo of our in vitro findings. Specific Aim 1: testing the hypothesis in vitro that apoCIII promotes foam cell formation and activation in macrophages We will examine whether apoCIII promotes lipid uptake in macrophages. We will then address in vitro the role of LOX-1 in apoCIII-triggered lipid accumulation. We will also examine apoCIII-induced expression of atherogenic molecules in macrophages. We will further explore mechanistic insights in vitro by determining the signaling mechanisms mediating these effects. Specific Aim 2: testing the hypothesis in vivo that apoCIII promotes foam cell formation and macrophage activation We will administer apoCIII to hyperlipidemic LDL-receptor deficient mice to determine in vivo whether this apolipoprotein promotes formation of atheromata rich in activated macrophage foam cells as examined by comprehensive histomorphological and biochemical assays and advanced imaging approaches. We will also examine in vivo whether apoCIII accelerate development of features typical of atheromata prone to acute complications.
|Effective start/end date||07/01/2009 → 06/30/2012|