Inhibition of Sirtuin‐1 Ameliorates Vascular Remodeling and Hypertension in SHR

Abstract

Sirtuin‐1 (SIRT1), class III histone deacetylase, has been shown to be overexpressed in hearts from spontaneously hypertensive rats (SHR). We recently showed that vascular smooth muscle cells (VSMC) from SHR exhibit enhanced expression of SIRT1 as compared to age‐matched Wister Kyoto (WKY) rats and contribute to the upregulation of Giα proteins implicated in the pathogenesis of hypertension. The present study was undertaken to investigate the role of upregulated SIRT1 expression in the pathogenesis of hypertension and associated vascular remodeling in SHR and to explore the underlying molecular mechanisms involved in this response. For this study, a selective inhibitor of SIRT1, EX‐527 (5mg/kg of body weight) was injected intraperitoneally into 8‐week‐old adult SHR and age‐matched WKY rats twice per week for 3 weeks. The blood pressure (BP) and heart rate was measured twice a week by the CODA™ non‐invasive tail cuff method. Treatment of SHR with Ex‐527 attenuated high BP by 50 mmHg and inhibited the augmented heart rate. The overexpression of Giα proteins in heart, VSMCs and aorta was also attenuated to the control levels by EX‐527. In addition, inhibition of SIRT1 also attenuated the enhanced levels of superoxide anion, NADPH oxidase activity, enhanced phosphorylation of c‐Src and ERK1/2/AKT in VSMCs isolated from EX‐527 treated SHR. Furthermore, the decreased expression of endothelial nitric oxide synthase (eNOS) in VSMCs and aorta from SHR was also restored to control levels by EX‐527. The hyperproliferation and hypertrophy exhibited by VSMC from SHR, the enhanced expression of cell cycle proteins cyclin D1 and cdk4 and Gqα /PLCβ1 proteins were also attenuated by EX‐527 treatment. These results suggest that the overexpression of SIRT1 contributes to the development of high BP and vascular remodeling in SHR and its inhibition improves hypertension and vascular remodeling. It may thus be suggested that inhibitors of SIRT1 may have the potential to be used as therapeutic agents in the treatment of cardiovascular complications associated with hypertension.Support or Funding InformationSupported by grant from Canadian Institutes of Health Research (CIHR)