β-Migrating Very Low Density Lipoprotein Attenuates Endothelium-Dependent Relaxation in Rabbit Atherosclerotic Aortas

Abstract

We studied the effects of β-migrating very low density lipoprotein (β-VLDL) on the vascular responses of isolated thoracic aortic preparations taken from normal and hypercholesterolemic rabbits. The endothelium-dependent relaxation induced by acetylcholine or adenosine triphosphate (ATP) was attenuated in the arteries from hypercholesterolemic rabbits that were fed a cholesterol-rich diet for 12 weeks. In these aortas, the lesional circumference of the atherosclerotic plaques (fatty streaks) was only 12.18 ± 1.98 %. The relaxation induced by the Ca²⁺ ionophore A23187 or nitroglycerin was not altered. Preincubation with β-VLDL significantly inhibited the relaxation due to acetylcholine, ATP, or A23187, especially in the aortas of hypercholesterolemic rabbits. However, β-VLDL did not alter the response to nitroglycerin. Preincubation with high density lipoprotein had no significant effect on vessel relaxation. These results indicated that endothelium-dependent relaxation was already inhibited in the early stages of atherosclerosis, and that the atherogenic lipoprotein, β -VLDL, further inhibited endothelium-dependent relaxation in atherosclerotic aortas. It may be that β -VLDL also plays a role in determining the level of vascular tonus in atherosclerosis.

Cholesterol Enrichment Impairs Capacitative Calcium Entry, eNOS Phosphorylation & Shear Stress-Induced NO Production

“…A number of studies have shown that hypercholesterolemia leads to impaired agonist-stimulated 10,19,23 and flow-dependent vasodilation. 19,45 Thus, we sought to understand the role of cholesterol enrichment in endothelial dysfunction.…”

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

“…Whole-body nitric oxide production also decreases with age ( 50,51 ), coincident with a decrease in LDL clearance rates ( 52,53 ). The ability of lipoproteins to inhibit eNOS activity ( 54,55 ) likely explains part of the correlation between LDL-cholesterol and nitric oxide production; however, the correlation is much stronger in individuals with two normal LDLR alleles than in individuals with a defective LDLR allele ( 49,56 ), suggesting that nitric oxide also promotes LDLR function. In support of this conclusion, transgenic overexpression of eNOS in apoE-defi cient mice decreases LDL-cholesterol levels ( 57,58 ).…”

HMG-CoA reductase inhibitor stabilizes rabbit atheroma by increasing basal NO and decreasing superoxide

“…ATHEROSCLEROTIC PLAQUES prone to rupture were found to be rich in lipids, and fibrous plaques were found to be difficult to rupture (1,20). Furthermore, ϳ70-80% of myocardial infarctions was found to occur in nonsignificant stenotic vessels (7,33).…”