Takayuki Iwaki, Research Assistant Professor

Atherosclerosis has been described as a “self-perpetuating” inflammatory disease which progresses in discrete stages and involves a number of cell types and effector molecules. Lipid metabolic disorders are heavily involved in the genesis and progression of atherosclerosis in humans, and thrombotic complications substantially contribute to the coronary artery disease that frequently accompanies atherosclerosis. Through the introduction of genetic mutations in mice, spontaneous models of atherosclerosis have emerged. A mouse model of human atherosclerosis with elevated LDL-cholesterol is one in which both the LDLR and APOBEC1 genes are deleted (LDLR-/-/APOBEC1-/-), since these mice lack the ability to convert apoB-100 to apoB-48 in liver and also are defective in LDL clearance. These doubly-deficient mice slowly and progressively present with severe spontaneous atherosclerosis on a normal chow diet, exhibit high levels of apoB-100-LDL-containing hypercholesterolemia, more closely mirroring the plasma lipid situation in humans.

A number of clinical and basic research studies have identified a relationship between hypercholesterolemia and endothelial dysfunction and accelerated atherosclerosis. Clinically, it has been determined that Fg levels and the net fibrinolytic activity are correlated with the degree of intimal thickening. Our laboratory has generated PAI-1, FG, and PG deficient mice in LDLR-/-/APOBEC1-/- background and they are now being analyzed to determine their role in the development and progression of atherosclerosis.