Wednesday, April 23, 2025
4/23/2025
RNA methylation in the progress of heart failure - PROJECT SUMMARY: Cardiovascular diseases are leading cause of morbidity and mortality in the US. Cardiac fibrosis is a fundamental mediator of heart failure progression. Following myocardial stress, fibroblasts are activated, resulting in extracellular matrix deposition in the heart's different regions and leading to cardiac fibrosis and subsequent cardiac dysfunction. Thus, understanding the molecular mechanisms underlying cardiac fibrosis is crucial for developing effective therapies. Several signaling cascades have been identified as key regulators of fibrosis. Among these, b-catenin-mediated activation of profibrotic genes expression is crucial in the progress of cardiac fibrosis. However, the precise mechanism that regulates b-catenin nuclear translocation (a key step for b-catenin-mediated fibrosis) during cardiac injury remains incompletely understood. The premise of this proposal is based on the strong preliminary data that confirm the contribution of RAPGEF5 (a guanine nucleotide exchange factor) mRNA methylation in the regulation of β-catenin nuclear translocation and its impact on the progress of cardiac fibrosis. RNA modifications, specifically methylation, are known to be important in regulating mRNA stability, splicing, and translation, but their role in cardiac fibrosis is not well studied. The central hypothesis of this application is that activation of METTL3 by TAC (pressure overload) leads to increased stability of RAPGEF5 mRNA, which promotes β-catenin translocation into the nucleus, resulting in the activation of fibrotic genes and progress of cardiac fibrosis. We hypothesize that inhibiting or deleting METTL3 will mitigate adverse cardiac remodeling by reducing fibrosis. In Aim 1, we will investigate the direct link between METTL3 activation and cardiac fibrosis progression using a fibroblast-specific METTL3 transgenic mouse model subjected to pressure overload-induced heart failure. In Aim 2, we will elucidate the mechanisms by which METTL3 regulates RAPGEF5 mRNA stability and β- catenin-mediated fibrotic signaling. This will involve overexpressing METTL3 in fibroblasts both in vivo and in vitro, followed by examination of RAPGEF5 and β-catenin expression, stability, and fibrotic signaling. Finally, in Aim 3, we will explore the therapeutic potential of inhibiting METTL3 in a mouse model of pressure overload-induced heart failure. We will treat mice with a pharmacological inhibitor of METTL3 (STM2457), either before the onset of heart failure (prevention strategy) or two weeks after (treatment strategy), and then assess various biochemical parameters as described in Aims 1 and 2.
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