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 c holesterol-rich LDL leads to the migration and recruitment of monocyte s, which then differentiate into macrophages after taking up large amo unts of oxidatively modified LDL via their scavenger receptors and bec ome lipid-laden 'foam cells' within the subendothelial space. It is ge nerally accepted that oxidized LDL and hyperlipidaemia impair endothel ial-dependent vascular relaxation, yet the existing literature on the effects of oxidatively modified LDL on endothelium-derived nitric oxid e (NO) and prostacyclin (PGI(2)) release is inconclusive, since oxidiz ed LDL has been reported to enhance or reduce NO and PGI(2) production . Our studies using cultured human endothelial and smooth muscle cells have established that basal rates of L-arginine (NO precursor) transp ort, NO and PGI(2) production and soluble guanylyl cyclase activity ar e unaffected by pretreatment (for 1 or 24 h) with native LDL, or with mildly or highly oxidized LDL. In contrast, highly oxidized LDL inhibi ted histamine-stimulated release of NO and PGI(2) from human endotheli al cells and induced an adaptive increase in the level of intracellula r glutathione in human smooth muscle cells, a response which was preve nted by the chain-breaking antioxidant a-tocopherol. Although initial rates of L-arginine transport and basal NO and PGI(2) release from hum an endothelium are unaffected by oxidized LDL, agonist-stimulated rele ase of these vasodilators is markedly attenuated. Elucidation of the m echanisms regulating these responses and their sensitivity to dietary antioxidants could lead to alternative strategies for reducing atherog enesis.