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

Abstract

SUMMARYLow 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 x-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.

Smooth Muscle Cells Influence Monocyte Response to LDL as well as Their Adhesion and Transmigration in a Coculture Model of the Arterial Wall

“…Therefore, a decreased production of NO in our cocultures in the presence of LDL might have contributed to the increased adhesion of THP-1 cells in cocultures when compared to the monocultures. There is, however, no general consensus about the effects of LDL on NO synthesis since oxLDL have been reported either to decrease or to increase cNOS expression [32]. Both in mono- and in coculture, we did not find any influence of LPC or oxLDL on NO release in the presence of THP-1 cells.…”

Improvement of Endothelial Dysfunction in Acromegaly after Transsphenoidal Surgery

“…It has been reported that patients with acromegaly have increased plasma concentrations of cholesterol [22], lipoprotein (a) and small dense LDL [23,24], and patients with hypercholesterolemia have impaired endothelium-dependent vasodilatation [25,26]. In fact, it has been shown that oxidized LDL-C impairs NO production [27], which plays a key role in the development of endothelial dysfunction and atherosclerosis [28] by production of reactive oxygen species [29].…”

Pravastatin Protection from Cold Stress in Myocardium of Rats.

“…47,48) Pravastatin stimulates an increase in nitric oxide (NO) production by cultured endothelial cells similar to the effects seen with acetylcholine. 48) It has been suggested that increased plasma LDL inhibits the active transport of L-arginine (L-ARG) by endothelial cells, 49) uncoupling the L-ARG: eNOS pathway and leading to superoxide anion production. 50) Because both superoxide anion and its reaction product NO, and peroxynitrite produce tissue injury, 51) it is possible that an indirect action of pravastatin may be present to normalize endothelial function by protecting the active arginine transport from injury by LDL, thereby preventing the formation of both superoxide anion and peroxynitrite.…”