The Role And Mechanism Of SIRT1 In Vascular Remodeling In Pulmonary Hypertension

Rationale:Pulmonary arterial hypertension (PAH) is a heterogenous syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, which leads to right ventricular (RV) failure. Despite aggressive treatments, the mortality of PAH remains high. Current therapies can hardly prevent from progression of PAH. Vascular remodeling is the key pathology of PAH. Proliferation of pulmonary arterial smooth muscle cells (PASMC) is the cytological basis of vascular remodeling. Inhibition of PASMC proliferation might contribute to the regression of PAH.Objective:To investigate the role of SIRT1, a class Ⅲ histone deacetylase, in the regulation of human pulmonary arterial smooth muscle cells (HPASMCs) proliferation and vascular remodeling in monocrotaline induced PAH rats.Methods:With realtime-PCR and western blot, we examined the expression of SIRT1in HPASMCs stimulated with PDGF-BB. FCM was applied to detect the effects of SIRT1on HPASMCs proliferation in vitro. After over-expression of RNAi to SIRT1, expression of cell cycle protein which functions in G1state, potassium channels proteins including Kv1.5and Kv2.1were examined by western blot or realtime-PCR. Furthermore, rats were injected with monocrotaline (MCT) to developed pulmonary arterial hypertension and resveratrol (2.5mg/kg per day or20mg/kg per day) was feeded orally. We investigated the efficacy of resveratrol to prevent from developing pulmonary arterial hypertension by hemodynamics, HE staining, immunohistochemistry, EVG staining and TUNEL assay. At last,the expressions of SIRT1, Kv1.5, Kv2.1and p21in the lungs of rats were detected by realtime-PCR or western blot.Results:We found that the expression of SIRT1in HPASMCs decreased after PDGF-BB stimulation. Adenoviral overexpression of SIRT1inhibited HPASMCs proliferation and led to an arrest of the cells in phase G1. In addition, SIRT1decreased the expression of CyclinDl, CyclinE, CDK2, increased the expression of p21,the G1phase regulatory protein.Meanwhile, SIRT1increased the expression of Kv1.5and Kv2.1. Moreover, resveratraol, SIRT1angonist could attenuat MCT induced pulmonary arterial remodeling and increased SIRT1, Kvl.5, Kv2.1and p21in the lungs of rats, which lead to improvement of pulmonary arterial hypertension.Conclusion:Our studies show that SIRT1decreases the expression of CyclinD1, CyclinE and CDK2, increases the expression of Kv1.5and Kv2.1, which result in inhibition of HPASMCs proliferation. Resveratraol, the angonist of SIRT1, exerts antiproliferative effects in the pulmonary arteries, which may contribute to the prevention of pulmonary arterial hypertension...