Poster abstracts
Poster number 10 submitted by Lisa Dorn
The mRNA methyltransferase, METTL3, regulates cardiac hypertrophy
Lisa E. Dorn (Department of Physiology and Cell Biology, The Ohio State University), Jop H. van Berlo (Cardiovascular Division, University of Minnesota), Chuan He (Department of Chemistry, University of Chicago), Federica Accornero (Department of Physiology and Cell Biology, The Ohio State University)
Abstract:
Cardiac hypertrophy is a risk factor for developing heart failure, and cardiac hypertrophy is mediated by increased synthesis of specific proteins in cardiomyocytes. Although significant progress has been made in understanding the transcriptional changes occurring in the remodeling heart, very little is known about how post-transcriptional events control the synthesis of maladaptive proteins in the stressed myocardium. The most abundant mRNA post-transcriptional modification is N6-methyladenosine (m6A), catalyzed by Methyltransferase-like 3 (METTL3). m6A levels are increased in human failing hearts, as well as in isolated neonatal rat cardiomyocytes (NRCMs) subjected to hypertrophic stimuli. To determine m6A’s role in cardiac remodeling, we generated a mouse model for cardiomyocyte-specific METTL3 overexpression and found that increasing m6A methylation is sufficient to promote cardiomyocyte hypertrophy. Specifically, mice overexpressing METTL3 have increased heart weight to body weight and tibia length ratios under baseline conditions. Analyses of cardiac cross-sections in these mice demonstrate increased cardiomyocyte area without a concurrent increase in fibrosis or other degenerative remodeling. METTL3-mediated hypertrophy suggests that, conversely, cardiac METTL3 knockdown may prevent hypertrophy. We adopted a loss of function approach through siRNA-mediated METTL3 silencing in NRCMs as well as a cardiomyocyte-specific METTL3 knockout mouse line. Reducing METTL3 prevents cardiomyocyte hypertrophy and blunts expression of pro-hypertrophic markers in isolated cells exposed to hypertrophic stimuli, and METTL3 knockout mice demonstrate cardiac structural and functional changes with aging consistent with heart failure and an inability to undergo physiological hypertrophy. Our recent findings support a role of METTL3 in modulating the cardiac hypertrophic response, and suggest METTL3 as a potential therapeutic target in the management of hypertrophy in heart failure.
Keywords: hypertrophy, m6A