Arg972 insulin receptor substrate-1 is associated with elevated plasma endothelin-1 level in hypertensives

OBJECTIVES: To explore the association among Arg(972) insulin receptor substrate-1 (IRS-1), hypertension, insulin resistance, and plasma levels of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1). METHODS: A total of 1030 patients, including 521 healthy controls, 142 patients with both primary hypertension and insulin resistance, 184 patients with primary hypertension but no insulin resistance, and 183 patients with insulin resistance but no hypertension were genotyped for the Arg(972) IRS-1 polymorphism. Serum levels of ET-1 and eNOS were determined by ELISA. Shear stress was applied to human umbilical vein endothelial cells (HUVECs) overexpressing wild type IRS-1 or Arg(972) IRS-1, and the mRNA and secreted protein levels of ET-1 were measured by real-time RT-PCR and ELISA, respectively. RESULTS: There was no significant difference in allelic frequency between patients with and without primary hypertension or insulin resistance, in the hypertensives, heterozygous Arg(972) IRS-1 carriers had significantly higher plasma ET-1 levels and blood pressure (BP) than the homozygous carriers. Although shear stress decreased ET-1 expression in control HUVECs as well as cells transfected with wild type Arg(972) IRS-1, it increased the mRNA dose-dependently and secreted protein levels of ET-1 in cells transfected with Arg(972) IRS-1. CONCLUSIONS: Based on both in-vivo and in-vitro data, we have shown a potential causal association between Arg(972) IRS-1 and elevated plasma ET-1 level in hypertensives, which may account for the aggravated hypertension observed in hypertensives with heterozygous Arg(972) IRS-1. This study for the first time provides insights into the role of Arg(972) IRS-1 in hypertension.