Oxidized LDL and HDL: antagonists in atherothrombosis

Increased LDL oxidation is associated with coronary artery disease. The pre dictive value of circulating oxidized LDL is additive to the Global Risk As sessment Score for cardiovascular risk prediction based on age, gender, tot al and HDL cholesterol, diabetes, hypertension, and smoking. Circulating ox idized LDL does not originate from extensive metal ion-induced oxidation in the blood but from mild oxidation in the arterial wall by cell-associated lipoxygenase and/or myeloperoxidase. Oxidized LDL induces atherosclerosis b y stimulating monocyte infiltration and smooth muscle cell migration and pr oliferation. It contributes to atherothrombosis by inducing endothelial cel l apoptosis, and thus plaque erosion, by impairing the anticoagulant balanc e in endothelium, stimulating tissue factor production by smooth muscle cel ls, and inducing apoptosis in macrophages. HDL cholesterol levels are inver sely related to risk of coronary artery disease. HDL prevents atheroscleros is by reverting the stimulatory effect of oxidized LDL on monocyte infiltra tion. The HDL-associated enzyme paraoxonase inhibits the oxidation of LDL. PAF-acetyl hydrolase, which circulates in association with HDL and is produ ced in the arterial wall by macrophages, degrades bioactive oxidized phosph olipids. Both enzymes actively protect hypercholesterolemic mice against at herosclerosis. Oxidized LDL inhibits these enzymes. Thus, oxidized LDL and HDL are indeed antagonists in the development of cardiovascular disease.