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Author Nanao-Hamai, Michiko ♦ Son, Bo-Kyung ♦ Hashizume, Tsuyoshi ♦ Ogawa, Sumito ♦ Akishita, Masahiro
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ APOPTOSIS ♦ BIOLOGICAL RECOVERY ♦ ESTROGENS ♦ GENES ♦ INHIBITION ♦ MUSCLES ♦ MYOCARDIAL INFARCTION ♦ PLANT GROWTH ♦ RECEPTORS ♦ WOMEN
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. - Highlights: • E2 inhibits Pi-induced calcification in vascular smooth muscles cells. • E2 inhibits Pi-induced apoptosis by restoration of Gas6-mediated survival pathway. • Gas6 transactivation by E2 is mediated by ERα.
ISSN 0006291X
Educational Use Research
Learning Resource Type Article
Publisher Date 2016-11-18
Publisher Place United States
Journal Biochemical and Biophysical Research Communications
Volume Number 480
Issue Number 3


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