High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men

Abstract

Background-Hypercholesterolemia is a risk factor for atherosclerosis-causing endothelial dysfunction, an early event in the disease process. In contrast, high-density lipoprotein (HDL) cholesterol inversely correlates with morbidity and mortality representing a protective effect. Therefore, we investigated the effects of reconstituted HDL on endothelial function in hypercholesterolemic men. Methods and Results-Endothelium-dependent and -independent vasodilation to intraarterial acetylcholine and sodium nitroprusside (SNP), respectively, was measured by forearm venous occlusion plethysmography in healthy normo-and hypercholesterolemic men. In hypercholesterolemics, the effects of reconstituted HDL (rHDL; 80 mg/kg IV over 4 hours) on acetylcholine-and SNP-induced changes in forearm blood flow were assessed in the presence or absence of the nitric oxide (NO) synthase inhibitor L-NMMA. Hypercholesterolemics showed reduced vasodilation to acetylcholine but not to SNP compared with normocholesterolemics (PϽ0.0001). rHDL infusion increased plasma HDL cholesterol from 1.3Ϯ0.1 to 2.2Ϯ0.1 mmol/L (PϽ0.0001, nϭ18) and significantly enhanced the acetylcholine-induced increase in forearm blood flow without affecting that induced by SNP. rHDL infusion also improved flow-mediated dilation of the brachial artery (to 4.5Ϯ0.9% from 2.7Ϯ0.6%, Pϭ0.02). NO synthase inhibition prevented the improvement in acetylcholine-induced vasodilation while leaving the response to SNP unchanged. Albumin infusion in an equivalent protein dose had no effect on vasomotion or lipid levels. Conclusions-In hypercholesterolemic patients, intravenous rHDL infusion rapidly normalizes endotheliumdependent vasodilation by increasing NO bioavailability. This may in part explain the protective effect of HDL from coronary heart disease and illustrates the potential therapeutic benefit of increasing HDL in patients at risk from atherosclerosis.

High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation

“…The ApoAI then moves to the Golgi and binds eNOS, a process that actively recruits the necessary initiating enzymes, such as AMPK, which phosphorylates and activates the enzyme. A similar in vivo mechanism (of eNOS activation by ApoAI) is supported by human clinical studies in which it was reported that acute infusions of ApoAI phospholipid discs (reconstituted HDL) can completely normalize the decreased vasomoter response in vessels of the forearm of hypocholesterolemic men (35,36). These outcomes were a result of direct restoration of the NO pathway.…”

Linking erectile dysfunction and coronary artery disease

“…15 There are emerging data suggesting that high-density lipoprotein may independently and favorably effect endothelial function. [59][60][61] The effects of hypertriglyceridemia, however, are less clear.…”

Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation

“…One of them is their beneficial effect on endotheliumdependent vasorelaxation. The intravenous administration of reconstituted HDL either to hypercholesterolaemic men or to heterozygotes deficient in ATP-binding cassette A1, both of whom had initially impaired endothelium-dependent vasorelaxation, restored normal vasorelaxation [3,4]. More particularly, ex vivo experiments on isolated strips of rabbit thoracic aorta showed that HDL are able to counteract the inhibitory effect of oxidised LDL (ox-LDL) on endothelium-dependent vasorelaxation [5].…”