The Research Of 17β-estradiol In Cardiovascular Protection And Its Molecular Mechanisms

Backgroud:Estrogen has extensive biological effect including against hypertension, atherosclerosis, lipid peroxidation and vascular injury, which play a pivotal role in cardiovascular protection. Vascular endothelial disfunction and myocardial metabolic disorder have been implicated in the pathogenesis of cardiovascular disease(CVD). Menopause means ovarian function failure and downstream estrogen levels. Premenopausal women are less risk of cardiovascular disease than men, the risk increase after menopause, similar to male. The International Menopause Society (IMS) in 2013 pointed out that perimenopausal and postmenopausal women with utilization of menopause hormone therapy (MHT) early can improve vessel function, lower cholesterol levels, regulate glycometabolism and blood pressure, which has potential cardiovascular protective effect, but the specific mechanism is unclear. Chronic inflammation and oxidative stress, is a central pathology physiology of the cardiovascular disease. Monocyte chemotactic factor 1 (MCP-1) inducts, regulates other formation and release of inflammatory factor, the formation of cascade, mediating inflammation, therefore it is considered to be the start of the inflammatory response factor. Induction of MCP-1, monocyte/macrophage activation and the accumulation of the subcutaneous is a key factor of atherosclerosis. RhoA belongs to Rho guanosine triphosphatase family, participating in maintaining vascular endothelium and the myocardial cytoskeleton structure, which plays an important role in regulation of cell migration. In recent years, studies have shown that SIRT1 can inhibit oxidative stress, inflammation, apoptosis, promote glucolipid metabolism, cell DNA damage repair, atherosclerosis, myocardial ischemia, myocardial hypertrophy and pathological processes of cardiovascular disease. AMP activated protein kinase (AMPK) is a cellular energy switch, adjust the AMP/ATP ratio, promote the mitochondrial oxidative metabolism of the generation, and participate in the energy of the muscle cell regulation. In addition, AMPK enhance SIRT1 activity by raising levels of NAD+in cells. AMPK/SIRT1 is involved in cellular energy metabolism process. Cellular experimental and clinical studies confirmed that exogenous estrogen can decrease the gene and protein expression of RhoA and MCP-1 in the vascular endothelial cells and smooth muscle cells but the specific mechanism is unclear. Current research has confirmed that the exogenous estrogen can modulate AMPK/SIRT1 pathway, but with the downstream signaling molecules (MCP-1 and RhoA) relationship is unclear.Objective:The aim of this study was to investigate the cardiovascular protective effects of exogenous estrogen in ovarietomized female Sprague-Dawley rats.Methods:Forty 12-week-old female rats were randomly divided into four groups:the blank control group (CON, n= 10), the treated group with 17β-estradiol (OVX+E2, n= 10), the ovariectomized control group (OVX, n= 10) and the Sham-operated group (Sham, n= 10). The rats in the Treated group were given 100μg/kg/d 17β-estradiol intragastric administration while other three groups were given the amount of physiological saline daily. After 16 weeks treatment, plasma was taken to assess serum the level of estradiol (E2), follicle stimulating hormone (FSH), monocyte chemotactic factor 1 (MCP-1) and RhoA; Silence regulating protein 1 (SIRT1), activated protein kinase (AMPK) expression in the homogenates of cardiac tissue were estimated by ELISA. Expression of MCP-1 and RhoA in the homogenates of cardiac tissue were detected by immunofluorescence histochemistry method.Results:Expression of MCP-1 and RhoA of OVX+E2 group in rats serum and cardiac tissues were significantly lower as compared to OVX group (p<0.05). Expression of SIRT1, AMPK of OVX+E2 group in the rats cardiac tissues were significantly higher than OVX group (p<0.05)Conclusion:17β-estradiol suppressed MCP-1, RhoA expression in female ovariectomized rats serum and cardiac tissues to exert the effects of cardiovascular protection. Upregulation of AMPK/SIRT1 of 17β-estradiol may be involved in attenuating MCP-1 and RhoA.