Abstract 13476: Selective Estrogen Receptor Modulator Retards Arterial Senescence and Atherosclerosis Through Restoration of Down-regulated Sirt-1 in Post-menopause Model Mouse
Background: Incidence of cardiovascular disease (CVD) increases with development of arterial senescence and atherosclerosis, which are accelerated after menopause in women. This study aims 1) to clarify the mechanism of which post-menopose facilitates arterial senescence and atherosclerosis, and 2) to develop optical treatment.
Methods and Results: Female Apolipoprotein E deficient (ApoE KO) mice underwent ovariectomy at 8 weeks old were used as post-menopausal model mice (PM). Age-matched female mice with sham operation were used as control (Ctr). We confirmed that serum estrogen concentration was significantly lower in PM than in Ctr. Twelve weeks after surgery, aortas were harvested to examine molecular biological analysis. Sirt-1 and the ratio of p-eNOS/eNOS protein expressions were significantly lower in PM than in Ctr. Ratio of senescence associated β galactosidase (SA-β Gal) positive cells and expressions of acetyl (Ac)-p53, p21, p16, and PAI-1 were significantly higher in PM than in Ctr. Aortic atherosclerotic lesions assessed by Oil Red O staining was significantly greater in PM than in Ctr. Sirt-1 overexpression retarded ovariectomy-induced arterial senescence. These results suggest that ovariectomy accelerates arterial senescence and atherosclerotic development through downregulation of Sirt-1. Next, we administrated selective estrogen receptor modulator (SERM) to PM mice. Sirt-1 and the ratio of p-eNOS/eNOS protein expression were significantly higher in SERM-treated PM mice than in untreated mice. Ratio of SA-β Gal positive cells, protein expressions of Ac-p53, p21, p16, and PAI-1, and aortic atherosclerotic lesions were significantly lower in SERM-treated PM mice than in untreated mice. The effect of SERM on arterial senescence and atherosclerosis was attenuated by administration of either L-NAME, eNOS inhibitor, or sirtinol, Sirt-1 inhibitor. In addition, L-NAME administration decreased Sirt-1 expression in SERM-treated PM mice, suggesting that SERM-induced eNOS activation upregulates Sirt-1.
Conclusion: SERM retards development of arterial senescence and atherosclerosis by activation of eNOS and Sirt-1 in postmenopause mice.
Author Disclosures: T. Miyauchi: None. Y. Ikeda: None. Y. Akasaki: None. M. Iwabayashi: None. Y. Sasaki: None. M. Miyata: None. M. Ohishi: None.
- © 2014 by American Heart Association, Inc.