Direct and Indirect Involvement of MicroRNA-499 in Clinical and Experimental Cardiomyopathy
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: 1. Define the associations between regulated miR-499 level in clinical and experimental heart disease and modulation of its predicted mRNA targets. 2. Determine the consequences of increased cardiac miR-499 on direct mRNA targeting, indirect mRNA modulation, and on myocardial protein content and post-translational 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 RISC- 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 HSP90 and PP1α
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 post-translational modification of myocardial proteins.
- Received January 26, 2012.
- Accepted June 29, 2012.
- Copyright © 2012, American Heart Association