MicroRNA-350 induces pathological heart hypertrophy by repressing both p38 and JNK pathways

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• 作者：Yuzhi Ge^a ; ^b ; ^e ; ¹ ; Shujuan Pan^a ; ^b ; ^c ; ¹ ; Di Guan^c ; ^d ; Hong Yin^b ; Yong Fan^c ; Jingjing Liu^c ; Shuhua Zhang^b ; Hongjie Zhang^c ; Lili Feng^b ; Yunxia Wang^b ; Ruxiang Xu^a ; ^{zjxuruxiang@163.com} ; James Q. Yin^a ; ^c ; ^{jqwyin@sun5.ibp.ac.cn} ; ^{Jamesyin2010@126.com}
• 关键词：Micro RNA ; Cardiac hypertrophy ; Apoptosis ; Gene expression ; Signaling pathway
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：1832
• 期：1
• 页码：1-10
• 全文大小：1368 K

文摘

Recent studies have identified important roles for microRNAs (miRNAs) in many cardiac pathophysiological processes, including the regulation of cardiomyocyte hypertrophy. However, the role of miR-350 in the cardiac setting is still unclear. The objective of this study is to determine whether miR-350 alone can induce pathological cardiac hypertrophy by repressing the SAPK pathway in cardiomyocytes. Here we report that miR-350 plays a key role in determining pathological cardiomyocyte hypertrophy and apoptosis. Comprehensive microarray profiling of miRs and qPCR showed that this unique miRNA was significantly up-regulated in rat hearts in response to late-stage transverse aortic constriction. Western blotting and luciferase assays confirmed that the target mRNAs of miR-350 are mitogen activated protein kinase (MAPK) 11/14 and MAPK8/9 gene transcripts. Gain-of-unction and loss-of-function approaches were used to investigate the functional roles of miR-350. The forced over-expression of miR-350 was sufficient to induce hypertrophy of cardiomyocytes through the posttranslational suppression of p38 and JNK protein synthesis. Moreover, miR-350 led to an increase in unphosphorylated NFATc3 and its nuclear translocation, resulting in the over-expression of pathological hypertrophy markers. As predicted, these effects could effectively be imitated by siR-JNK/p38 through the degeneration of p38 and JNK mRNAs. Conversely, antagomir-350 could lower the levels of miR-350, reverse the expression of target proteins and reduce cell size and apoptosis relative to the administration of mutant antagomir-350. Our data provide the first evidence that miR-350 is a critical regulator of pathological cardiac hypertrophy and apoptosis in rats.