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.
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 hypertrophiedhuman hearts and associated with decreased levels of predicted target mRNAs. Likewise, miR-499 is increased in Gq-mediated murinecardiomyopathy. Forced cardiomyocyte expression of miR-499 at levels comparable to humancardiomyopathy induced progressive murineheart 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-499cardiomyopathy phenotype, including of heat shock protein 90 and protein serine/threonine phosphatase 1-α. CONCLUSIONS:miR-499 is increased in human and murinecardiac hypertrophy and cardiomyopathy, is sufficient to cause murineheart 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.
Authors: Scot J Matkovich; Derek J Van Booven; Keith A Youker; Guillermo Torre-Amione; Abhinav Diwan; William H Eschenbacher; Lisa E Dorn; Mark A Watson; Kenneth B Margulies; Gerald W Dorn Journal: Circulation Date: 2009-02-23 Impact factor: 29.690
Authors: Daehyun Baek; Judit Villén; Chanseok Shin; Fernando D Camargo; Steven P Gygi; David P Bartel Journal: Nature Date: 2008-07-30 Impact factor: 49.962
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