title: Cardiac hypertrophy is positively regulated by MicroRNA miR-23a.
abstract: MicroRNAs (miRNAs) are a class of small noncoding RNAs that mediate post-transcriptional gene silencing. Myocardial hypertrophy is frequently associated with the development of heart failure. A variety of miRNAs are involved in the regulation of cardiac hypertrophy, however, the molecular targets of miRNAs in the cardiac hypertrophic cascades remain to be fully identified. We produced miR-23a transgenic mice, and these mice exhibit exaggerated cardiac hypertrophy in response to the stimulation with phenylephrine or pressure overload by transverse aortic banding. The endogenous miR-23a is up-regulated upon treatment with phenylephrine, endothelin-1, or transverse aortic banding. Knockdown of miR-23a attenuates hypertrophic responses. To identify the downstream targets of miR-23a, we found that transcription factor Foxo3a is suppressed by miR-23a. Luciferase assay indicates that miR-23a directly inhibits the translation activity of Foxo3a 3' UTR. Introduction or knockdown of miR-23a leads to the alterations of Foxo3a protein levels. Enforced expression of the constitutively active form of Foxo3a counteracts the provocative effect of miR-23a on hypertrophy. Furthermore, we observed that miR-23a is able to alter the expression levels of manganese superoxide dismutase and the consequent reactive oxygen species, and this effect is mediated by Foxo3a. In addition, our results show that miR-23a and Foxo3a bi-transgenic mice exhibit a reduced hypertrophic response compared with the miR-23a transgenic mice alone. Our present study reveals that miR-23a can mediate the hypertrophic signal through regulating Foxo3a. They form an axis in hypertrophic machinery and can be targets for the development of hypertrophic treatment.
authors.affiliation: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Lin
authors.affiliation: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Long
authors.affiliation: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: peifli@ioz.ac.cn.
authors.forename: Pei-Feng
authors.initials: PF
authors.lastname: Li
mesh_terms: D000818:Animals; D001483:Base Sequence; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse
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