Chylomicron-remnant-like particles inhibit receptor-mediated endothelium-dependent vasorelaxation in pig coronary arteries

Abstract

The influence of native and oxidized chylomicron-remnant-like particles (CMR-LPs) on endothelium-dependent relaxation in pig coronary arteries was studied. Artificial lipid particles of a size and lipid composition resembling chylomicron remnants and containing pig apolipoprotein E were used to investigate the effects of chylomicron remnants on the relaxation of isolated segments of pig coronary arteries in response to three endothelium dilators: 5-hydroxytryptamine (5-HT), bradykinin and the calcium ionophore A23187. CMR-LPs caused significant inhibition of the maximum relaxation response of the vessels to 5-HT, but not that to bradykinin or A23187 ( P <0.05). In contrast, CMR-LPs that had been oxidized by incubation with 10 microM CuSO(4) (oxidized CMR-LPs) were found to significantly reduce maximal relaxation to bradykinin by 13% ( P <0.05) and to reduce the sensitivity of the tissue to A23187 by 1.7-fold ( P <0.05). In experiments in which either the L-arginine/nitric oxide (NO) pathway or the endothelium-derived hyperpolarizing factor (EDHF) pathway was selectively inhibited, leaving the other intact, the inhibitory effect of oxidized CMR-LPs was observed only in vessels in which the -arginine/NO-mediated pathway was operative. Furthermore, the oxidized particles had no inhibitory effect on the relaxation of the vessel segments to the non-endothelium-dependent agonists S -nitro- N -acetylpenicillamine, 5'-( N -ethylcarboxamido)adenosine or pinacidil. These results demonstrate that CMR-LPs inhibit vascular relaxation in pig coronary arteries by an endothelium-dependent mechanism involving the L-arginine/NO pathway, but not the EDHF pathway, and provide evidence in support of a role for chylomicron remnants in the endothelial dysfunction associated with hypercholesterolaemia and atherogenesis.

Chylomicron-remnant-like particles modify production of vasoactive mediators by endothelial cells

“…In contrast, the early PGI 2 release observed in remnant-stimulated cells was not affected by NS-398 treatment and is probably mediated through COX-1 activation. eNOS expression was not modified by CMR-LP treatment, indicating that changes in enzyme expression are unlikely to account for the remnantmediated decrease in basal cGMP observed in the present study, or in previous studies in whole vessels [3,8,10]. Exposure of HUVECs to CMR-LPs caused a rapid activation of the ERK1/2 family of mitogen-activated protein kinases, whose activation has been implicated in regulating COX-2 expression.…”

“…Briefly, a lipid mixture (50 mg) comprising 70% (w/w) trilinolein, 25% (w/w) phospholipid, 3% (w/w) cholesteryl oleate and 2% (w/w) cholesterol in 0.9% NaCl in Tricine buffer (20 mM, pH 7.4) was emulsified by sonication, and apolipoprotein E (ApoE) was transferred from human serum on to the appropriately sized particles [10]. The CMR-LPs resembled physiological CMRs in size, density and lipid composition, and had triacylglycerol/total cholesterol ratios of (4.01 ± 0.76):1 (n = 19 preparations).…”

“…size, density and lipid composition to physiological CMRs have comparable effects on porcine coronary arteries, with CMR-LPs inhibiting basal NO production, and oxidized remnant particles suppressing both basal and agonist-induced NO formation [10].…”

Protection of chylomicron remnants from oxidation by incorporation of probucol into the particles enhances their uptake by human macrophages and increases lipid accumulation in the cells

“…The size, density and lipid composition of the CRLPs used was similar to that of physiological remnants [40,41], and they also contained human apoE. Extensive previous studies in both humans and experimental animals have shown that model particles of this type are cleared from the blood and metabolized in a similar way to the corresponding physiological lipoproteins [42–45], and CRLPs containing apoE from the appropriate species have also been found to have effects which mimic those of physiological remnants in rat hepatocytes and pig endothelial cells [40,46–48]. As lipophilic antioxidants can easily be incorporated into the model particles, CRLPs provide a suitable and convenient model for our experiments.…”

Chylomicron remnants: mediators of endothelial dysfunction?

“…Several pharmacological studies in rat and porcine vessels have now shown that CRLPs inhibit relaxation and potentiate vasoconstriction in an endothelium-dependent manner which is mediated, at least partly, by impaired generation of the vasodilator molecule NO (nitric oxide) [6,7]. Evidence that these particles also reduce basal NO production by cultured porcine ECs was subsequently provided [8].…”