title: Protective effects of estrogen against vascular calcification via estrogen receptor α-dependent growth arrest-specific gene 6 transactivation.
abstract: Vascular calcification is one of the major complications of cardiovascular disease and is an independent risk factor for myocardial infarction and cardiac death. Postmenopausal women have a higher prevalence of vascular calcification compared with premenopausal women, suggesting protective effects of estrogen (E2). However, the underlying mechanisms of its beneficial effects remain unclear. In the present study, we examined the inhibitory effects of E2 on vascular smooth muscle cell (VSMC) calcification, and found that growth arrest-specific gene 6 (Gas6), a crucial molecule in vascular calcification, is transactivated by estrogen receptor α (ERα) in response to E2. In human aortic smooth muscle cells, physiological levels of E2 inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner. This inhibitory effect was significantly abolished by MPP, an ERα-selective antagonist, and ERα siRNA, but not by PHTPP, an ERβ-selective antagonist, and ERβ siRNA, implicating an ERα-dependent action. Apoptosis, an essential process for Pi-induced VSMC calcification, was inhibited by E2 in a concentration-dependent manner and further, MPP abolished this inhibition. Mechanistically, E2 restored the inhibited expression of Gas6 and phospho-Akt in Pi-induced apoptosis through ERα. Furthermore, E2 significantly activated Gas6 transcription, and MPP abrogated this E2-dependent Gas6 transactivation. E2-BSA failed to activate Gas6 transcription and to inhibit Ca deposition in VSMC, suggesting beneficial actions of genomic signaling by E2/nuclear ERα. Taken together, these results indicate that E2 exerts inhibitory effects on VSMC apoptosis and calcification through ERα-mediated Gas6 transactivation. These findings indicate a potential therapeutic strategy for the prevention of vascular calcification, especially in postmenopausal women.
authors: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Michiko
authors: M
authors: Nanao-Hamai
authors: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Institute of Gerontology, The University of Tokyo, Tokyo, Japan.
authors: Bo-Kyung
authors: BK
authors: Son
authors: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Tsuyoshi
authors: T
authors: Hashizume
authors: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Sumito
authors: S
authors: Ogawa
authors: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: akishita-tky@umin.ac.jp.
authors: Masahiro
authors: M
authors: Akishita
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000008:administration & dosage*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D016896:Treatment Outcome; D061205:Vascular Calcification / Q000378:metabolism* / Q000517:prevention & control*; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D036341:Intercellular Signaling Peptides and Proteins; D000099255:Growth Arrest-Specific Protein 6
keywords: Calcification; Estrogen; Genomic action; Growth arrest-specific gene 6