Estrogen modulates vascular smooth muscle cell function through downregulation of SIRT1

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// Chien-Hsing Lee 1 , Sheng-Chiang Su 1 , Chi-Fu Chiang 2 , Chu-Yen Chien 2 , Chia-Chen Hsu 2 , Tzu-Yi Yu 3 , Shih-Ming Huang 3 , Yi-Shing Shieh 4 , Hong-Wei Kao 5 , Chien-Sung Tsai 6 , Yi-Jen Hung 1 and Chih-Yuan Lin 6 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 3 Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan 4 Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 5 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 6 Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Correspondence to: Chih-Yuan Lin, email: linrock@ms26.hinet.net Keywords: estrogen; sirtuin 1 (SIRT1); vascular smooth muscle cell; ovariectomy Received: September 13, 2017 Accepted: October 27, 2017 Published: November 10, 2017 ABSTRACT Background: There are sex differences in the incidence and severity of cardiovascular disease. Although an estrogen-mediated vasculoprotective effect is widely accepted, clinical trial results have been conflicting and the detailed mechanisms are still unclear. Sirtuin 1 (SIRT1), a class III histone deacetylase, may protect against vascular aging and atherosclerosis; however, the effects of estrogen on SIRT1 expression and vascular smooth muscle cell (VSMC) behavior remain unknown. Materials and Methods: We ovariectomized (OVX) female, wild-type, C57BL/6J mice, which were randomized into non-estrogen- and estrogen-supplemented groups. We also treated A7r5 VSMCs with 17-β-estradiol and resveratrol, a SIRT1 activator, in vitro , and measured the expression of SIRT1 and apoptotic markers, as well as proliferation, viability, and migration. Results: Aortic tissue from OVX mice exhibited marked VSMC hyperplasia and upregulation of SIRT1, which was reversed by 17-β-estradiol supplementation, as assessed by western blotting and immunohistochemical staining. In vitro , 17-β-estradiol downregulated SIRT1 expression in a dose- and time-dependent manner, increased apoptosis, and reduced proliferation, viability, and migration. Resveratrol reversed these effects through the activation of SIRT1. Estrogen appeared to mediate its effects through the Akt and ERK pathways. Conclusions: Estrogen may regulate cardiovascular health via the expression of SIRT1, possibly through the AKT and ERK signaling pathways.

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