摘要(英) |
Cardiovascular diseases (CVDs) are the first leading cause of death globally. According to the statistics by the World Health Organization, an estimated 17.7 million people died from CVDs in 2016. This reflects the big impacts of CVDs on global mortality rate besides human health. Although development of CVDs can be respectively regulated by microRNA-494 (miR-494) and green tea (-)-epicatechin (EC), it is still unknown whether EC interacts with miR-494 on CVDs. The present thesis was designed to use transverse aortic banding (TAB)-induced mice and H9c2 rat cardiocytes and investigate whether EC improved cardiac hypertrophy and fibrosis through the miR-494 pathway. We confirmed that mice with TAB for 2 and 12 weeks caused cardiac dysfunctions, including increased blood flow velocity, blood pressure, IVSd, IVSs, LVPWd, and LVPWs, while cardiac LVFS and LVEF were decreased at 12 weeks. At 12 weeks, TAB also induced increases in heart weight, fibrosis. At 2 and 12 weeks, TAB induced increases cardiac hypertrophic marker genes, such as β-MHC, ANP, and BNP, but decrease α-MHC. Besides, fibrosis marker genes, such as Col1α2 and Col3α1, induced at 2 and 12 weeks. In addition, TAB induced an increase of miR-494 RNA expression in mice heart after 3, 7, 14, and 21 days but not 1 day of treatment, while the miR-494-downregulated gene ATF3 was increased with mRNA levels at day 1 and then significantly declined to the basal levels at day 3 until day 21. Treatment with EC (0.25 mg/kg/d) antagonized 12-week-TAB-induced decreases in cardiac LVFS and LVEF. Also, EC suppressed TAB-induced increases in levels of β-MHC, ANP and miR-494 RNA levels in the heart. Moreover, EC improved TAB-induced cardiac fibrosis, maybe via inhibited Col1α2 and Col3α1 at 2 weeks; in addition, Col3α1 held down at 12 weeks. Interestingly, EC had no effect on heart weight in TAB-treated mice. In parallel, miR-494-transgenic mice with TAB for 12 weeks exhibited slightly greater level of cardiac fibrosis and significantly less percentages of LVFS and LVEF compared with non-transgenic mice with TAB. But, no significant changes were observed in the heart weight. Moreover, treatment with 1 mg EC/mice/2d improved the percentages of LVFS and LVEF in miR-494-transgenic mice with 12-week TAB. Using H9c2 cardiocytes, we found that pretreatment with 5 μM of EC blocked angiotensin-II-induced increases of miR-494 RNA levels. According to these in vivo and in vitro findings, we conclude that EC improves TAB-induced heart disease through inhibition of miR-494 expression. Results of this thesis also led us to understand how consumption of EC-containing green tea protects humans against the risk of CVDs. |
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