Otitodilichukwu Ojukwu

Introduction. Heart disease is the leading cause of death in the United States. Heart disease presents itself in many forms clinically and is apparent in many patient populations. Heart failure is a progressive disease that occurs after multiple ischemic and traumatic events to the cardiac tissue. Several studies have focused on understanding epigenetic regulators of heart functioning and its contribution to heart failure. Methyltransferase like 3 (Mettl3) in particular is a m6A mRNA modifier that has been studied extensively and has shown promise in regulating heart pathology. RNA influences many aspects of biology through activities that are attributable to its epigenetic modifications. The N6-Methyladenine (m6A) modification is the most abundant and reversible modification on mRNA and Mettl3 plays an essential role on mRNA modification. Its regulation in cardiomyocytes can be utilized in understanding heart disease. Methods. Two mouse line were generated alongside a control. One mouse group that overexpressed Mettl3 and the other that had Mettl3 knocked out (METTL3-cKO). Control mice were compared to METTL3-cKO and to Mettl3 overexpression at varying months. Echocardiogram function test were measured for each mouse line with and without an invasive cardiac procedure such as TAC. Global Metll3 expression levels in other non-cardiomyocyte specific tissues were also measured. Results. The results showed that Mettl3 overexpression induces compensated hypertrophic remodeling of the heart without inducing cardiac functional deficits either at baseline or under cardiac stress. Conversely Mettl3^-/- showed a severe decrease in cardiomyocyte cross-sectional area with maladaptive eccentric cardiac remodeling. Global Mettl3^-/- post MI showed CM proliferation and adaptive repair, suggesting improved heart function without Mettl3 expression. Conclusions. This further emphasizes the diverse roles Mettl3 plays in regulating heart diseases and the multiple ways Mettl3 can be an epigenetic regulator in heart functioning. By targeting its role in m6A on cardiomyocytes, Mettl3 modifications on m6A mRNA can be used as a treatment for a diverse set of myocardial injury.

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