ABSTRACT
BACKGROUND: Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for familial hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these familial hypoalphalipoproteinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL. METHODS AND RESULTS: In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and -independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase NG-monomethyl-l-arginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.4+/-0.2 mmol/L; P<0.05), and their forearm blood flow responses to both 5HT (maximum, 49.0+/-10.4%) and L-NMMA (maximum, -22.8+/-22.9%) were blunted compared with control subjects (both P< or =0.005). Infusion of apoA-I/PC disks increased plasma HDL to 1.3+/-0.4 mmol/L in ABCA1 heterozygotes, which resulted in complete restoration of vasomotor responses to both 5HT and L-NMMA (both P
Subject(s)
Apolipoprotein A-I/administration & dosage , Endothelium, Vascular/drug effects , Lipoproteins, HDL/blood , Recovery of Function/drug effects , Tangier Disease/therapy , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , Adult , Blood Flow Velocity/drug effects , Cohort Studies , Dose-Response Relationship, Drug , Drug Carriers/administration & dosage , Endothelium, Vascular/physiopathology , Enzyme Inhibitors/pharmacology , Female , Forearm/blood supply , Humans , Infusions, Intravenous , Male , Middle Aged , Mutation , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase Type III , Nitroprusside/pharmacology , Phosphatidylcholines/administration & dosage , Serotonin/pharmacology , Tangier Disease/blood , Tangier Disease/physiopathology , Treatment Outcome , Vasodilator Agents/pharmacologyABSTRACT
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 (P<0.0001). rHDL infusion increased plasma HDL cholesterol from 1.3+/-0.1 to 2.2+/-0.1 mmol/L (P<0.0001, n=18) 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 4.5+/-0.9% from 2.7+/-0.6%, P=0.02). 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 endothelium-dependent 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.
