Impaired endothelial function in never-treated hypertensive subjects carrying the Arg972 polymorphism in the insulin receptor substrate-1 gene.
Some cardiovascular risk factors, such as hypertension and insulin resistance, are associated with endothelial dysfunction. Insulin regulates both in vitro and in vivo expression of endothelial nitric oxide synthase (eNOS) via a pathway involving insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3 kinase. Recently, we found that human endothelial cells obtained from carriers of the Arg(972) IRS-1 polymorphism exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. To investigate a possible relationship between Arg(972) IRS-1 polymorphism and endothelial dysfunction in vivo, we enrolled a cohort of 100 never-treated hypertensive subjects. Endothelium-dependent and endothelium-independent vasodilation were assessed by increasing doses of acetylcholine and sodium nitroprusside. IRS-1 polymorphism was detected by PCR. The allelic frequency of the Arg(972) IRS-1 variant was 8.0%. Stratifying subjects according to IRS-1 genotype, we observed that acetylcholine-stimulated forearm blood flow was significantly (P < 0.0001) lower in Gly/Arg heterozygous carriers than in Gly/Gly carriers (11.3 +/- 4.4 vs. 14.7 +/- 5.9 ml/100 ml(-1) of tissue per min(-1)). Sodium nitroprusside caused comparable increments in forearm blood flow in both groups (12.9 +/- 2.4 vs. 13.3 +/- 3.5 ml/100 ml(-1) of tissue per min(-1)). Our data strongly suggest that, by inducing endothelial dysfunction, the Arg(972) IRS-1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease.
Perticone
Francesco
F
Department of Experimental and Clinical Medicine, G. Salvatore University Magna Graecia of Catanzaro, Policlinico Mater Domini-Via Tommaso Campanella, 88100 Catanzaro, Italy. perticone@unicz.it
Sciacqua
Angela
A
Scozzafava
Angela
A
Ventura
Giorgio
G
Laratta
Emanuela
E
Pujia
Arturo
A
Federici
Massimo
M
Lauro
Renato
R
Sesti
Giorgio
G
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000483:Alleles; D001120:Arginine; D015331:Cohort Studies; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D014665:Vasodilator Agents; D009599:Nitroprusside; D001120:Arginine; D000109:Acetylcholine