Cytotoxicity of Remnants of Triglyceride-Rich Lipoproteins: An Atherogenic Insult?

Abstract

One of the more widely accepted hypotheses (1) to explain the develop ment of atherosclerosis is that some form of functional and/or structural injury occurs to endothelial cells that line the lumen of the artery. This injury disrupts the permeability barrier and may lead to an infiltration of plasma components (lipoproteins) into the artery and an adherence of circulating blood cells (monocytes and platelets) to the injured endothelium. The conversion of monocyte-derived macrophages to lipid laden foam cells has been thought to play a central role in the development of atherosclerotic lesions. Although the importance of endothelial cell injury in the initiation of the atherogenic process has been demonstrated by the development of atherosclerotic lesions in the artery following mechanical (balloon catheter) injury of the endothelium (2), the factor(s) responsible for the injury of arterial endothelium in vivo is not currently clear. Ross and Harker (3) suggested that hypercholesterolemia might cause endothelial cell damage, and so set off a sequence of reactions, which results in an atherosclerotic lesion (4). Although there is currently no strong evidence that hypercholsterolemia indeed leads to endothelial cell damage in vivo, several investigators have reported a cytotoxic effect of LDL and VLDL on cultured endothelial cells (5–9). The cytotoxic effect of LDL has been indicated to be a result of lipid peroxidation (6–7). Lipid peroxides have been identified in the sera of healthy men, hypercholesterolemia and hypertriglyceridemia subjects, and diabetic patients (10–12), but sera from these subjects were unable to produce cytotoxicity to cultured human endothelial cells (12).