Li Cui, Li Xuelian, Gao Xu, Zhang Ruixue, Zhang Ying, Liang Haihai, Xu Chaoqian, Du Weijie, Zhang Yong, Liu Xue, Ma Ning, Xu Zhidan, Wang Leimin, Chen Xu, Lu Yanjie, Ju Jiaming, Yang Baofeng, Shan Hongli
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang 150081, PR China; Department of Biochemistry, Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
Int J Cardiol. 2014 May 1;173(2):268-76. doi: 10.1016/j.ijcard.2014.02.035. Epub 2014 Feb 28.
Cardiac hypertrophy is a primary predictor of progressive heart disease that often results in heart failure. Growing evidence has demonstrated that microRNAs (miRNAs) play a critical role in regulating cardiac hypertrophy. This study was designed to evaluate the effect of miR-328 on cardiac hypertrophy and the potential molecular mechanisms. We found that transgenic overexpression of miR-328 in the heart induced cardiac hypertrophy in mice, which was accompanied by reduced SERCA2a level increased intracellular calcium concentration and calcineurin protein level, and enhanced NFATc3 nuclear translocation. However, normalization of miR-328 level by its antisense chemically modified with locked nucleic acid (LNA-antimiR-328) reversed the changes. Forced expression of miR-328 resulted in cardiomyocyte hypertrophy in cultured neonatal rat ventricular cells, which was accompanied by downregulation of SERCA2a expression and activation of the calcineurin/NFATc3 signaling pathway. These changes were abolished by LNA-antimiR-328. We validated the SERCA2a as a direct target for miR-328. MiR-328 expression was upregulated in cardiomyocyte treated with isoproterenol (ISO) to induce hypertrophy; while knockdown of miR-328 attenuated the hypertrophic responses. The level of miR-328 was significantly elevated in a mouse model of hypertrophy by thoracic aortic banding (TAC). Consistently, SERCA2a was downregulated, whereas calcineurin were upregulated, and NFATc3 nuclear translocation was enhanced. In contrast, hypertrophy in these mice was significantly alleviated when treated with miR-328 antisense. MiR-328 promotes cardiac hypertrophy by targeting SERCA2a. Our study therefore uncovered a novel molecular mechanism for cardiac hypertrophy and indicated miR-328 as a potential therapeutic target for this cardiac condition.
心肌肥厚是进展性心脏病的主要预测指标，常导致心力衰竭。越来越多的证据表明，微小RNA（miRNA）在调节心肌肥厚中起关键作用。本研究旨在评估miR-328对心肌肥厚的影响及其潜在的分子机制。我们发现，心脏中miR-328的转基因过表达诱导小鼠心肌肥厚，同时伴有肌浆网钙ATP酶2a（SERCA2a）水平降低、细胞内钙浓度升高、钙调神经磷酸酶蛋白水平升高以及活化T细胞核因子c3（NFATc3）核转位增强。然而，用锁核酸化学修饰的反义miR-328（LNA-antimiR-328）使miR-328水平恢复正常可逆转这些变化。miR-328的强制表达导致培养的新生大鼠心室细胞肥大，同时伴有SERCA2a表达下调和钙调神经磷酸酶/NFATc3信号通路激活。LNA-antimiR-328消除了这些变化。我们验证了SERCA2a是miR-328的直接靶点。用异丙肾上腺素（ISO）处理诱导肥大的心肌细胞中miR-328表达上调；而敲低miR-328可减弱肥大反应。在胸主动脉缩窄（TAC）所致的肥大小鼠模型中，miR-328水平显著升高。同样，SERCA2a下调，而钙调神经磷酸酶上调，NFATc3核转位增强。相反，用miR-328反义核酸处理这些小鼠可显著减轻肥大。miR-328通过靶向SERCA2a促进心肌肥厚。因此，我们的研究揭示了心肌肥厚的一种新的分子机制，并表明miR-328是这种心脏疾病的潜在治疗靶点。
