For more than two decades, there has been continuing evidence of lipid oxidation playing a central role in atherogenesis. The oxidation hypothesis of atherogenesis has evolved to focus on specific proinflammatory oxidized phospholipids that result from the oxidation of LDL phospholipids containing arachidonic acid and that are recognized by the innate immune system in animals and humans. These oxidized phospholipids are largely generated by potent oxidants produced by the lipoxygenase and myeloperoxidase pathways. The failure of antioxidant vitamins to influence clinical outcomes may have many explanations, including the inability of vitamin E to prevent the formation of these oxidized phospholipids and other lipid oxidation products of the myeloperoxidase pathway. Preliminary data suggest that the oxidation hypothesis of atherogenesis and the reverse cholesterol transport hypothesis of atherogenesis may have a common biological basis. The levels of specific oxidized lipids in plasma and lipoproteins, the levels of antibodies to these lipids, and the inflammatory/antiinflammatory properties of HDL may be useful markers of susceptibility to atherogenesis. Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides may both promote a reduction in oxidized lipids and enhance reverse cholesterol transport and therefore may have therapeutic potential. (1) reported that the oxidation of LDL was injurious to artery wall cells and suggested that LDL oxidation may be important in atherogenesis. They also demonstrated that HDL inhibited the LDL-induced cytotoxicity (1). Over the ensuing two decades, this group elucidated the basis for these observations and established the important role of oxidized cholesterol products, especially cholesterol hydroperoxides (2). THE SEARCH FOR MECHANISMS OF LDL-INDUCEDFOAM CELL FORMATION Also in 1979, Goldstein et al. (3) reported that acetylated LDL but not native LDL was taken up by "scavenger receptors" instead of the LDL receptor, resulting in cholesteryl ester accumulation in macrophages characteristic of foam cells. Because acetylation was not known to occur, after the publication of this seminal paper there was a search for physiological ligands that would explain foam cell formation. Fogelman et al. (4) soon reported that malondialdehyde, an obligate product of the oxidation of arachidonic acid by the lipoxygenase pathways, could cause Schiff-base formation with the epsilon amino groups of apolipoprotein B (apoB) lysines in LDL. The altered lipoprotein was recognized by macrophage scavenger receptors, resulting in cholesteryl ester accumulation characteristic of foam cells. The next year, Steinberg and colleagues (5) demonstrated that cultured endothelial

The ability of high-density lipoprotein (HDL) to promote cholesterol efflux is thought to be important in its protection against cardiovascular disease. Anti-inflammatory properties of HDL have emerged as additional properties that may also be important. HDL appears to have evolved as part of the innate immune system functioning to inhibit inflammation in the absence of an acute phase response (APR) but functioning to increase inflammation in the presence of an APR. Inbred strains of mice that are genetically susceptible to atherosclerosis have pro-inflammatory HDL, while inbred strains that are resistant to atherosclerosis have anti-inflammatory HDL. In one small study, humans with coronary heart disease (CHD) or CHD equivalents had pro-inflammatory HDL prior to statin therapy and about half continued to have pro-inflammatory HDL after statin therapy despite a profound decrease in plasma lipids. Pro-inflammatory HDL was relatively weak in its ability to promote cholesterol efflux while anti-inflammatory HDL was better in promoting cholesterol efflux. In other studies, oxidative alterations of the major protein of HDL, apolipoprotein A-I (apoA-I), impaired the ability of the apoA-I to promote cholesterol efflux. Thus, HDL structure and function may be more important than HDL-cholesterol levels in predicting risk for cardiovascular disease.