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Modulation of vascular tone by low density lipoproteins: effects on L‐arginine transport and nitric oxide synthesis

Low density lipoprotein (LDL) plays an important role in atherogenesis. Focal accumulation within the arterial intima of excess amounts of cholesterol‐rich LDL leads to the migration and recruitment of monocytes, which then differentiate into macrophages after taking up large amounts of oxidatively modified LDL via their scavenger receptors and become lipid‐laden ‘foam cells’ within the subendothelial space. It is generally accepted that oxidized LDL and hyperlipidaemia impair endothelial‐dependent vascular relaxation, yet the existing literature on the effects of oxidatively modified LDL on endothelium‐derived nitric oxide (NO) and prostacyclin (PGI2) release is inconclusive, since oxidized LDL has been reported to enhance or reduce NO and PGI2 production. Our studies using cultured human endothelial and smooth muscle cells have established that basal rates of L‐arginine (NO precursor) transport, NO and PGI2 production and soluble guanylyl cyclase activity are unaffected by pretreatment (for 1 or 24 h) with native LDL, or with mildly or highly oxidized LDL. In contrast, highly oxidized LDL inhibited histamine‐stimulated release of NO and PGI2 from human endothelial cells and induced an adaptive increase in the level of intracellular glutathione in human smooth muscle cells, a response which was prevented by the chain‐breaking antioxidant alpha‐tocopherol. Although initial rates of L‐arginine transport and basal NO and PGI2 release from human endothelium are unaffected by oxidized LDL, agonist‐stimulated release of these vasodilators is markedly attenuated. Elucidation of the mechanisms regulating these responses and their sensitivity to dietary antioxidants could lead to alternative strategies for reducing atherogenesis.