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

Abstract

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.

• Authors: Yuzhi Ge, Shujuan Pan, Di Guan, Hong Yin, Yong Fan, Jingjing Liu, Shuhua Zhang, Hongjie Zhang, Lili Feng, Yunxia Wang, Ruxiang Xu, James Q Yin
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1832 Issue 1 Pg. 1-10 (Jan 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23000971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• MIRN350 microRNA, rat
• MicroRNAs
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4

Topics

• Animals
• Cardiomegaly (enzymology, genetics, pathology)
• Cell Line
• Down-Regulation
• Female
• Humans
• MAP Kinase Kinase 4 (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• MicroRNAs (genetics, metabolism)
• Myocytes, Cardiac (enzymology)
• Rats
• Signal Transduction
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)