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Circ Res. 2012 Aug 17;111(5):521-31. doi: 10.1161/CIRCRESAHA.112.265736. Epub 2012 Jun 29.

Direct and indirect involvement of microRNA-499 in clinical and experimental cardiomyopathy.

Author information

1
Department of Internal Medicine, Center for Pharmacogenomics, 660 S Euclid Ave, Campus Box 8220, St Louis, MO 63110, USA. smatkovi@dom.wustl.edu

Abstract

RATIONALE:

MicroRNA-499 and other members of the myomiR family regulate myosin isoforms in pressure-overload hypertrophy. miR-499 expression varies in human disease, but results of mouse cardiac miR-499 overexpression are inconsistent, either protecting against ischemic damage or aggravating cardiomyopathy after pressure overload. Likewise, there is disagreement over direct and indirect cardiac mRNAs targeted in vivo by miR-499.

OBJECTIVE:

To define the associations between regulated miR-499 level in clinical and experimental heart disease and modulation of its predicted mRNA targets and to determine the consequences of increased cardiac miR-499 on direct mRNA targeting, indirect mRNA modulation, and on myocardial protein content and posttranslational modification.

METHODS AND RESULTS:

miR-499 levels were increased in failing and hypertrophied human hearts and associated with decreased levels of predicted target mRNAs. Likewise, miR-499 is increased in Gq-mediated murine cardiomyopathy. Forced cardiomyocyte expression of miR-499 at levels comparable to human cardiomyopathy induced progressive murine heart failure and exacerbated cardiac remodeling after pressure overloading. Genome-wide RNA-induced silencing complex and RNA sequencing identified 67 direct, and numerous indirect, cardiac mRNA targets, including Akt and MAPKs. Myocardial proteomics identified alterations in protein phosphorylation linked to the miR-499 cardiomyopathy phenotype, including of heat shock protein 90 and protein serine/threonine phosphatase 1-α.

CONCLUSIONS:

miR-499 is increased in human and murine cardiac hypertrophy and cardiomyopathy, is sufficient to cause murine heart failure, and accelerates maladaptation to pressure overloading. The deleterious effects of miR-499 reflect the cumulative consequences of direct and indirect mRNA regulation, modulation of cardiac kinase and phosphatase pathways, and higher-order effects on posttranslational modification of myocardial proteins.

Comment in

PMID:
22752967
PMCID:
PMC3429338
DOI:
10.1161/CIRCRESAHA.112.265736
[Indexed for MEDLINE]
Free PMC Article

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