Abstract-As the major regulator of vascular homeostasis, the endothelium exerts a number of vasoprotective effects, such as vasodilation, suppression of smooth muscle cell growth, and inhibition of inflammatory responses. Many of these effects are largely mediated by nitric oxide, the most potent endogenous vasodilator. Nitric oxide opposes the effects of endothelium-derived vasoconstrictors and inhibits oxidation of low-density lipoprotein. A defect in the production or activity of nitric oxide leads to endothelial dysfunction, signaled by impaired endothelium-dependent vasodilation. Accumulating evidence suggests that endothelial dysfunction is an early marker for atherosclerosis and can be detected before structural changes to the vessel wall are apparent on angiography or ultrasound. Many of the risk factors that predispose to atherosclerosis can also cause endothelial dysfunction, and the presence of multiple risk factors has been found to predict endothelial dysfunction.

Lipoproteins play a central role in the development of atherosclerotic cardiovascular disease in humans. The plasma concentrations of lipoproteins and their metabolic fates are modulated by apolipoproteins on the surface of these lipid-rich particles. The hypothesis has been raised that genetic variation in apolipoproteins is a major determinant of the interindividual variation in susceptibility to coronary artery disease (CAD). In humans, the structural gene locus for plasma apolipoprotein E (apo E) is polymorphic:1 " 6 three common alleles, designated e4, e3, and e2, code for three major apo E isoforms in plasma, respectively designated apo E4, apo E3, and apo E2. Apo E is a key protein in the modulation of the metabolism of the highly atherogenic apo B-containing lipoproteins. Therefore, apo E provides a good model to test the above hypothesis.The existence of a polymorphism for such an important apolipoprotein has been a source of major interest in recent years and has raised many questions for clinicians, epidemiologists, geneticists, and biochemists. The similarities of the relative frequencies of the three common alleles among populations representing very different ethnic, cultural, and geographic settings; their different effects on •lipoprotein metabolism; and their association with certain lipid transport disorders have stimulated research aimed at a better understanding of their role in health and disease. A wealth of information 7 " 18 has accrued from studies on apolipoprotein E structure, metabolism, and function. These have considerably advanced our knowledge of the role of apo E in normal and abnormal lipoprotein metabolism, the complex interactions leading to hyperfipidemia and atherosclerosis, and the pathogenesis of type III hyperiipoproteinemia. Of major interest is the observation that the protein products of the e4 and E2 alleles have separate, and in some circumstances opposite, influences on plasma lipo- protein concentrations, a finding which leads to the hypothesis that the apo E polymorphism ranks among the major factors involved in determining interindividual differences in the initiation and progression of atherosclerosis. The evidence associating the apo E polymorphism with altered lipid and lipoprotein levels and atherosclerosis will be reviewed here. First, the apo E gene and gene product will be considered with a brief overview of molecular biology, protein chemistry, and methods for phenotyping. Second, the impact of variation at the apo E locus on plasma lipids and lipoproteins in health and disease will be discussed. Third, the metabolic interactions accounting for the various effects of the different alleles on lipids and lipoproteins will be considered to provide a unifying interpretation as to how apo E modulates the metabolism of apo B-containing lipoproteins and their remnants. Last, direct evidence associating the apo E polymorphism and atherosclerosis will be reviewed and discussed. This review is not intended to be all-inclusive, and the reader is referred to recent r...

ClinicalTrials.gov Identifier: NCT00240318.

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