Oxidative modification of low‐density lipoproteins and the inhibition of relaxations mediated by endothelium‐derived nitric oxide in rabbit aorta

Abstract

1 The mechanism by which Cu2f-oxidized low-density lipoproteins (oxLDL) inhibit acetylcholine (ACh)-evoked relaxations mediated by endothelium-derived nitric oxide (EDRF) in rabbit aortic rings was investigated. The proposed role of lysophosphatidylcholine (LPC) in the inhibition was also studied. 2 The kinetics of lipid peroxidation of native low-density lipoproteins (LDL) from individual donors, as measured by changes in conjugated diene concentration, were related to the inhibitory effects of the resultant oxLDL. It was found that the more susceptible LDL was to oxidation, the greater the inhibition. 3 No correlation was found between the inhibitory effects of oxLDL and LPC content. 4 Synthetic 1-palmitoyl LPC produced an inhibition of ACh-induced relaxations and when added to precontracted rings evoked nitric oxide-mediated endothelium-dependent relaxation. This latter effect was not elicited by oxLDL.5 Synthetic 1-palmitoyl (10 uM) had no effect on relaxations evoked by glyceryl trinitrate in endothelium-denuded aortic rings in contrast to the inhibition found previously for oxLDL. 6 Concentrations of oxLDL and phospholipase A2-treated LDL which inhibited relaxation contained very different LPC concentrations. Unlike oxLDL, the inhibitory effects of phospholipase A2-treated LDL preparations were independent of the donors and showed no lag period. 7 We sugggest that there are differences in the mechanisms by which oxLDL and 1-palmitoyl LPC exert their inhibitory effects on relaxation. 8 The inhibition of relaxation by oxLDL (1-2 mg protein ml-1) was prevented by the presence of high-density lipoproteins (HDL; 1-2 mg protein ml-1). 9 It is proposed that prevention of the inhibition of relaxation by HDL is consistent with the inhibitory factor(s) being lipophilic constituents of oxLDL. However, variations in the inhibitory effects of oxLDL preparations are not due to differences in their LPC content and factors other than LPC must contribute to the inhibition.

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

“…Moreover, the activity of iNOS in cytokine-activated cells appears to be critically dependent on availability and transport of exogenous L-arginine, even though intracellular concentrations of L-arginine exceed the Km (< 0. 1 mM) for iNOS (Bogle et al 1992 Ganz, 1996) and is supported by studies in vitro (Plane et al 1992). Native LDL inhibits endothelium-dependent relaxation in aortic ring preparations (Andrews, Bruckdorfer, Dunn & Jacobs, 1987), although oxidized LDL is more potent (Jacobs et al 1990).…”

“…Lysophosphatidylcholine and lipid hydroxy and hydroperoxy acids, generated during oxidative modification of LDL, have been implicated as key mediators of the LDL-induced inhibition of endothelium-dependent relaxation (Kugiyama et al 1990; Mangin, Kugiyama, Nguy, Kerns & Henry, 1993;Jacobs & Bruckdorfer, 1995). The precise mechanisms of action of native and oxidized LDL remain to be resolved (Galle et al 1991;Plane et al 1992). It seems likely that LDL scavenges NO released from endothelial cells, since the effect is reversed by antioxidants (Anderson et al 1996); another possibility is that LDL decreases the sensitivity of smooth muscle cells to NO in vascular beds prone to atherogenesis (Galle et al 1991).…”

Increased susceptibility to oxidation of low‐density lipoproteins isolated from patients with systemic sclerosis

“…It is possible that the LDL may have been subject to free radical attack as a consequence of the pathologic processes which prevail in this disease, rather than being part of the initiating stages. Nevertheless, it is thought that completion of the oxidative process takes place in the subendothelium in large vessel disease, because fluorescent antibodies to oxidized LDL demonstrate the presence of this material in large arteries (46), where it is very cytotoxic and impairs endothelial function (47). The oxidation of LDL may then exacerbate the pathologic changes occurring in these vessels.…”

Modulation of blood flow and tissue perfusion by endothelium‐derived relaxing factor

“…In atherosclerotic vessels dysfunction initially occurs at arterial bifurcations and in the proximal aorta, but extends to the microcirculation and therefore cannot be attributed simply to imposition of a diffusion barrier by intimal thickening (Ragazzi, Froldi, Pandolfo, Chinelatto, De Biasi, Prosdocimi, Caparrotta & Fassina, 1989;McLenachan, Vita, Fish, Treasure, Cox, Ganz & Selwyn, 1990;Flavahan, 1992;Kuo, Davis, Cannon & Chilian, 1992). Oxidized low-density lipoprotein may contribute by inactivating EDRF and inhibiting NOS (Mitchell, Warner, Huang, Forstermann & Murad, 1992;Plane, Bruckdorfer, Kerr, Steuer & Jacobs, 1992), and also contains lysophosphatidylcholine, which impairs endothelium-dependent relaxation by depleting Ca2" stores and disrupting receptor-G protein coupling (Inoue, Hirata, Yamada, Hamamori, Matsuda, Akita & Yokoyama, 1992;Flavahan, 1993). Indeed, the earliest pattern of abnormality mimics that induced by pertussis toxin in normal conduit vessels, suggesting a specific abnormality in Gi protein function (Flavahan, 1992).…”