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Impaired Endothelial Function in Never-Treated Hypertensive Subjects Carrying the Arg⁹⁷² Polymorphism in the Insulin Receptor Substrate-1 Gene

Department of Experimental and Clinical Medicine (F.P., A.Sci., A.Sco., G.V., E.L., A.P., G.S.), "G. Salvatore" University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy; and Department of Internal Medicine (M.F., R.L.), University of Rome-Tor Vergata, 00173 Rome, Italy

Address all correspondence and requests for reprints to: Francesco Perticone, M.D., Department of Medicina Sperimentale e Clinica, Policlinico Mater Domini-Via Tommaso Campanella, 88100 Catanzaro, Italy. E-mail: perticone{at}unicz.it.

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 Arg⁹⁷² 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 Arg⁹⁷² 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 Arg⁹⁷² 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 Arg⁹⁷² IRS-1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease.

This work was supported in part by grants from European Community "EuroDiabetesGene" Grants QLG1-CT-1999-00674 (to G.S.) and PRIN-COFIN 2000 MM06A92341-002 (to F.P.).

Abbreviations: ACh, Acetylcholine; BMI, body mass index; BP, blood pressure; eNOS, endothelial nitric oxide synthase; FBF, forearm blood flow; HOMA, homeostasis model assessment; HR, heart rate; IRS-1, insulin receptor substrate 1; PI-3, phosphatidylinositol-3; SNP, sodium nitroprusside; VR, vascular resistance.

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