title: 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.affiliation: Translational Medicine Program, the Military General Hospital of Beijing PLA, Beijing, China.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Ge
authors.forename: Shujuan
authors.initials: S
authors.lastname: Pan
authors.forename: Di
authors.initials: D
authors.lastname: Guan
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.forename: Yong
authors.initials: Y
authors.lastname: Fan
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.forename: Shuhua
authors.initials: S
authors.lastname: Zhang
authors.forename: Hongjie
authors.initials: H
authors.lastname: Zhang
authors.forename: Lili
authors.initials: L
authors.lastname: Feng
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Wang
authors.forename: Ruxiang
authors.initials: R
authors.lastname: Xu
authors.forename: James Q
authors.initials: JQ
authors.lastname: Yin
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C578571:MIRN350 microRNA, rat; D035683:MicroRNAs; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4