HDL and the inflammatory response induced by LDL-derived oxidized phospholipids

Oxidation of low density lipoprotein (LDL) phospholipids containing arachid onic acid at the sn-2 position occurs when a critical concentration of "see ding molecules" derived from the lipoxygenase pathway is reached in LDL. Wh en this critical concentration is reached, the nonenzymatic oxidation of LD L phospholipids produces a series of biologically active, oxidized phosphol ipids that mediate the cellular events seen in the developing fatty streak. Normal high density lipoprotein (HDL) contains at least 4 enzymes as well as apolipoproteins that can prevent the formation of the LDL-derived oxidiz ed phospholipids or inactivate them after they are formed. In the sense tha t normal HDL can prevent the formation of or inactivate these inflammatory LDL-derived oxidized phospholipids, normal HDL is anti-inflammatory. HDL fr om mice that are genetically predisposed to diet-induced atherosclerosis be came proinflammatory when the mice are fed an atherogenic diet, injected wi th LDL-derived oxidized phospholipids, or infected with influenza A virus. Mice that were genetically engineered to be hyperlipidemic on a chow diet a nd patients with coronary atherosclerosis, despite normal lipid levels, als o had proinflammatory HDL. It is proposed that HDL-derived oxidized phospho lipids and HDL may be part of a system of nonspecific innate immunity and t hat the detection of proinflammatory HDL may be a useful marker of suscepti bility to atherosclerosis.