From Fatty Streak to Myocardial Infarction.

Plaque rupture leads to thrombosis and myocardial infarction. The site of plaque rupture is usually at the shoulder of lesions that have many monocyte-macrophages characteristic of chronic inflammatory reactions. The Atherosclerosis Research Unit at UCLA has concentrated on studying the causes responsible for initiating this chronic inflammatory reaction in the artery wall. Using state-of-the-art ultrastructural techniques it was demonstrated that normal low density lipoproteins (LDL) are trapped in a three dimensional cage work of fibers and fibrils in the artery wall. Here the lipids in LDL are exposed to the oxidative wastes of the artery wall cells. Oxidation of the LDL phospholipids produces biologically active molecules that cause the expression of high levels of binding molecules on the endothelium and also leads to the expression of the genes and proteins for monocyte chemo-attractants and differentiation factors. The expression of these molecules initiates the monocytic infiltration and conversion of the monocytes into macrophages. Additionally, these phospholipids cause the expression of the potent coagulant - tissue factor. The induction of these molecules by the oxidized lipid is mediated in part by elevation of cyclic AMP levels and the activation of the transcription factor NFkB. High density lipoproteins (HDL) prevent the formation and/or destroy the biologically active lipids by the action of enzymes that are carried in HDL. Genetic studies indicate that the propensity to form biologically active oxidized lipids and or the ability to inactivate them is under the control of one or more major genes. Understanding the genetic and molecular basis for the inflammatory component of atherosclerosis will allow the development of new strategies for the prevention of myocardial infarction.