Macrophage Foam Cell Formation During Early Atherogenesis Is Determined by the Balance Between Pro-Oxidants and Anti-Oxidants in Arterial Cells and Blood Lipoproteins

Atherosclerosis is a multifactorial disease, where more than one mechanism, along more than one step, contributes to macrophage cholesterol accumulation and foam cell formation, the hallmark of early atherogenesis. Arterial macrophages take up oxidized low-density lipoproteins (Ox-LDL), leading to cellular accumulation of cholesterol and oxysterols. Atherogenic modifications of LDL include, in addition to oxidation, retention and aggregation. Intervention to inhibit LDL oxidation can affect the above additional LDL modifications. Indeed, we have demonstrated in the atherosclerotic apolipoprotein E-deficient mice that consumption of vitamin E or of flavonoids from red wine or licorice decreased LDL oxidation, LDL retention, and LDL aggregation and attenuated macrophage foam cell formation and atherosclerosis. The balance between pro-oxidants and anti-oxidants in the LDL particle (such as cholesteryl ester vs. vitamin E), as well as in arterial wall macrophages (such as NADPH oxidase vs. glutathione), determines the extent of LDL oxidation. Antioxidants can protect LDL from oxidation not only by their binding to the lipoprotein, but also following their accumulation in cells of the arterial wall. Whereas antioxidants can prevent the formation of Ox-LDL, human serum paraoxonase (PON 1), an HDL-associated esterase that hydrolyzes organophosphates, can eliminate oxidized LDL (by hydrolysis of its lipid peroxides), which is formed when antioxidant protection is not sufficient. Ox-LDL, in turn, can inactivate paraoxonase activity. Thus, the combination of antioxidants together with active paraoxonase decreases the formation of Ox-LDL and preserves PON1's ability to hydrolyze this atherogenic lipoprotein and hence, to attenuate atherosclerosis.