Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein.
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.


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</=0.001). Endothelium-independent vasodilation remained unaltered throughout the protocol.


CONCLUSIONS
In ABCA1 heterozygotes, isolated low HDL is associated with endothelial dysfunction, attested to by impaired basal and stimulated NO bioactivity. Strikingly, both parameters were completely restored after a single, rapid infusion of apoA-I/PC. These findings indicate that in addition to its long-term role within reverse cholesterol transport, HDL per se also exerts direct beneficial effects on the arterial wall.
Bisoendial
Radjesh J
RJ
Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
Hovingh
G Kees
GK
Levels
Johannes H M
JH
Lerch
Peter G
PG
Andresen
Irmgard
I
Hayden
Michael R
MR
Kastelein
John J P
JJ
Stroes
Erik S G
ES
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D016632:Apolipoprotein A-I / Q000008:administration & dosage*; D001783:Blood Flow Velocity / Q000187:drug effects; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007262:Infusions, Intravenous; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000008:administration & dosage; D020127:Recovery of Function / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D013631:Tangier Disease / Q000097:blood / Q000503:physiopathology / Q000628:therapy*; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000494:pharmacology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D004337:Drug Carriers; D004791:Enzyme Inhibitors; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; D014665:Vasodilator Agents; D009599:Nitroprusside; D012701:Serotonin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III