Deletion of miR-22 in mice blunted cardiac hypertrophy and remodeling in response to stress but sensitized them to the development of dilated cardiomyopathy.
miR-22 is a critical regulator of cardiomyocyte hypertrophy and remodeling, and its loss blunts hypertrophy but sensitizes to dilated cardiomyopathy under stress.
RATIONALE: The adult heart is composed primarily of terminally differentiated, mature cardiomyocytes that express signature genes related to contraction. In response to mechanical or pathological stress, the heart undergoes hypertrophic growth, a process defined as an increase in cardiomyocyte cell size without an increase in cell number. However, the molecular mechanism of cardiac hypertrophy is not fully understood. OBJECTIVE: To identify and characterize microRNAs that regulate cardiac hypertrophy and remodeling. METHODS AND RESULTS: Screening for muscle-expressed microRNAs that are dynamically regulated during muscle differentiation and hypertrophy identified microRNA-22 (miR-22) as a cardiac- and skeletal muscle-enriched microRNA that is upregulated during myocyte differentiation and cardiomyocyte hypertrophy. Overexpression of miR-22 was sufficient to induce cardiomyocyte hypertrophy. We generated mouse models with global and cardiac-specific miR-22 deletion, and we found that cardiac miR-22 was essential for hypertrophic cardiac growth in response to stress. miR-22-null hearts blunted cardiac hypertrophy and cardiac remodeling in response to 2 independent stressors: isoproterenol infusion and an activated calcineurin transgene. Loss of miR-22 sensitized mice to the development of dilated cardiomyopathy under stress conditions. We identified Sirt1 and Hdac4 as miR-22 targets in the heart. CONCLUSIONS: Our studies uncover miR-22 as a critical regulator of cardiomyocyte hypertrophy and cardiac remodeling.
Huang et al. (2013) studied Cardiac hypertrophy and remodeling. miR-22 deletion or overexpression vs. Control/wild-type was evaluated on Cardiac hypertrophy and remodeling in response to stress. Deletion of miR-22 in mice blunted cardiac hypertrophy and remodeling in response to stress but sensitized them to the development of dilated cardiomyopathy.