Abstract 320: Selective Estrogen Receptor Modulator Retards Arterial Senescence and Atherosclerosis via Upregulation of Sirt-1 and Autophagy 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 LC3II/LC3I 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, 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. Overexpression of either Sirt-1 or autophagy retarded arterial senescence in vitro. These results suggest that ovariectomy accelerates arterial senescence and atherosclerotic development through downregulation of Sirt-1 and autophagy. Next, we administrated selective estrogen receptor modulator (SERM) to PM mice. Sirt-1 and the ratio of LC3II/LC3I 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, and PAI-1, and aortic atherosclerotic lesions were significantly lower in SERM-treated PM mice than in untreated mice. The effect of SERM on augmentation of autophagy and inhibition of arterial senescence and atherosclerotic development was attenuated by administration of sirtinol, Sirt-1 inhibitor. Conclusion: SERM retards development of arterial senescence and atherosclerosis by activation of Sirt-1 and autophagy in postmenopause mice.