Resveratrol Ameliorates Cardiac Hypertrophy by Down-regulation of miR-155 Through Activation of Breast Cancer Type 1 Susceptibility Protein.
Resveratrol Ameliorates Cardiac Hypertrophy by Down-regulation of miR-155 Through Activation of Breast Cancer Type 1 Susceptibility Protein.
复制标题
白藜芦醇通过激活乳腺癌 1 型易感蛋白下调 miR-155，从而改善心脏肥大
DOI：
10.1161/jaha.115.002648
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发表时间：
2016-04-22
影响因子：
5.4
通讯作者：
Tu Y
中科院分区：
文献类型：
--
作者：
Fan Y;Liu L;Fang K;Huang T;Wan L;Liu Y;Zhang S;Yan D;Li G;Gao Y;Lv Y;Chen Y;Tu Y
据报道，多酚白藜芦醇（Rev）具有心脏保护作用，如抑制TAC（横向主动脉收缩）或异丙肾上腺素（ISO）诱导的肥大。发现MicroRNA-155（miR-155）在肥厚心肌中减少，Rev预处理可进一步减少。本研究旨在探讨miR-155对心肌肥厚的分子作用，重点关注乳腺癌1型易感蛋白（BRCA 1）的作用。我们证明Rev可以减轻TAC治疗心脏肥大小鼠模型中心肌肥大的严重程度。在压力超负荷或ISO诱导的肥厚性心肌细胞中观察到miR-155的下调。有趣的是，Rev的给药显著降低了心肌细胞中的miR-155水平。与其减少miR-155的作用一致，Rev通过激活心肌细胞中的BRCA 1缓解了心脏肥大并恢复了心脏功能。我们的研究结果进一步揭示了叉头盒O3 a（FoxO 3a）是心脏中的miR-155靶点。miR-155直接抑制FoxO 3a，其表达在体内和体外的miR-155 agomir和模拟治疗中减轻。我们得出结论，BRCA 1失活可以增加miR-155的表达，从而导致心脏肥大。Rev部分通过下调miR-155表达产生有益作用，这可能是治疗心肌肥大的新策略。
The polyphenol resveratrol (Rev) has been reported to exhibit cardioprotective effects, such as inhibition of TAC (transverse aortic constriction) or isoprenaline (ISO)‐induced hypertrophy. MicroRNA‐155 (miR‐155) was found to be decreased in hypertrophic myocardium, which could be further reduced by pretreatment of Rev. The study was designed to investigate the molecular effects of miR‐155 on cardiac hypertrophy, focusing on the role of breast cancer type 1 susceptibility protein (BRCA1). We demonstrated that Rev alleviated severity of hypertrophic myocardium in a mice model of cardiac hypertrophy by TAC treatment. Down‐regulation of miR‐155 was observed in pressure overload– or ISO‐induced hypertrophic cardiomyoctyes. Interestingly, administration of Rev substantially attenuated miR‐155 level in cardiomyocytes. In agreement with its miR‐155 reducing effect, Rev relieved cardiac hypertrophy and restored cardiac function by activation of BRCA1 in cardiomyoctyes. Our results further revealed that forkhead box O3a (FoxO3a) was a miR‐155 target in the heart. And miR‐155 directly repressed FoxO3a, whose expression was mitigated in miR‐155 agomir and mimic treatment in vivo and in vitro. We conclude that BRCA1 inactivation can increase expression of miR‐155, contributing to cardiac hypertrophy. And Rev produces their beneficial effects partially by down‐regulating miR‐155 expression, which might be a novel strategy for treatment of cardiac hypertrophy.