The dioxygenase TET2 regulates pathological cardiac hypertrophy

Aims

Heart failure (HF) is one of the most devastating consequences of cardiovascular diseases. Regardless of etiology, heart failure is often preceded by cardiac hypertrophy. In the present study we investigated the effect of cardiomyocyte-specific deletion of ten-and-eleven translocation 2 (TET2) on cardiac hypertrophy.

Methods and materials

Cardiac hypertrophy was induced in vitro by exposing cardiomyocytes to angiotensin II (Ang II), isoproterenol (ISO), or phenyleprine (PE) and in vivo by subjecting the mice to transverse aortic constriction (TAC).

Key findings

TET2 expression was elevated in cardiac tissues in animal models of cardiac hypertrophy, in cardiomyocytes exposed to pro-hypertrophic stimuli, and in HF patients. TET2 knockdown dampened the hypertrophic response in cultured cardiomyocytes treated with different pro-hypertrophic stimuli. Constitutive deletion of TET2 from cardiomyocytes in mice attenuated pathological hypertrophy and improved heart function in the trans-aortic constriction (TAC) model. In addition, induced deletion of TET2 after the onset of pathological hypertrophy similarly averted the pathogenic progression and rescued the decline of heart function.

Significance

TET2 may play an essential role mediating the hypertrophic response in cardiomyocytes. Screening for small-molecule compounds that selectively target TET2 can be considered as a reasonable approach for the intervention of heart failure.