Loss of microRNA-155 Protects the Heart from Pathological Cardiac Hypertrophy
Rationale: In response to mechanical and/or pathological stress, adult mammalian hearts often undergo mal-remodeling, a process commonly characterized as pathological hypertrophy, which is associated with upregulation of fetal genes, increased fibrosis, and reduction of cardiac dysfunction. The molecular pathways that regulate this process are not fully understood.
Objective: To explore the function of microRNA-155 (miR-155) in cardiac hypertrophy and remodeling.
Methods and Results: Our previous work identified miR-155 as a critical microRNA that repressed the expression and function of the myocyte enhancer factor 2A (MEF2A). In this study, we found that miR-155 is expressed in cardiomyocytes and that its expression is reduced in pressure overload-induced hypertrophic hearts. In mouse models of cardiac hypertrophy, miR-155 null hearts suppressed cardiac hypertrophy and cardiac remodeling in response to two independent pathological stressors - transverse aortic restriction (TAC) and an activated calcineurin (CnA) transgene. Most importantly, loss of miR-155 prevents the progress of heart failure and substantially extends the survival of CnA transgenic mice. The function of miR-155 in hypertrophy is confirmed in isolated cardiomyocytes. We identified Jarid2/jumonji as a miR-155 target in the heart. miR-155 directly represses Jarid2, whose expression is increased in miR-155 null hearts. Inhibition of endogenous Jarid2 partially rescues the effect of miR-155 loss in isolated cardiomyocytes.
Conclusions: Our studies uncover miR-155 as an inducer of pathological cardiomyocyte hypertrophy and suggest that inhibition of endogenous miR-155 might have clinical potential to suppress cardiac hypertrophy and heart failure.
- cardiac hypertrophy
- cardiomyocyte hypertrophy
- cardiac remodeling
- posttranscriptional regulation
- Received February 21, 2014.
- Revision received March 18, 2014.
- Accepted March 21, 2014.