Essential roles of lipoxygenases in LDL oxidation and development of atherosclerosis

Abstract

Oxidative modification of low-density lipoprotein (LDL) is one of the critical steps for the development of atherosclerosis. Accumulating studies have indicated that 12/15-lipoxygenase highly expressed in macrophages plays an essential role in the oxidation of circulating LDL. It has been demonstrated that LDL needs to bind the LDL receptor-related protein (LRP), a cell-surface receptor, prior to its oxidation by 12/15-lipoxygenase expressed in macrophages. LRP is suggested to mediate the selective transfer of cholesteryl ester in LDL to the plasma membrane of macrophages without endocytosis and degradation of the LDL particle. At the same time, binding of LDL to LRP translocates the 12/15-lipoxygenase from the cytosol to the plasma membrane. It is also demonstrated that 5-lipoxygenase localized in macrophages generates leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues and contribute to lesion development. Therefore, the inhibition of these lipoxygenases may be effective in the prevention and treatment of the inflammatory diseases.