Myocardial infarction (MI), one of the most severe types of
heart attack, exerts a strong negative effect on heart muscle by causing a massive and rapid loss of cardiomyocytes. However, the existing
therapies do little to improve cardiac regeneration. Due to the role of
methyltransferase-like 3 (METTL3) in the physiological proliferation of cardiomyocytes, we aimed to determine whether METTL3 could also promote cardiomyocyte proliferation under pathological conditions and to elucidate the underlying mechanism. The effects of METTL3 on cardiomyocyte proliferation and apoptosis were investigated in an in vivo rat model of MI and in an in vitro model of neonatal rat cardiomyocytes (NRCMs) exposed to
hypoxia. We found that METTL3 expression was downregulated in
hypoxia-exposed NRCMs and MI-induced rats. Furthermore, METTL3 pretreatment enhanced cardiomyocyte proliferation and inhibited cardiomyocyte apoptosis under hypoxic or MI conditions, and silencing METTL3 had the opposite effects. Additionally, METTL3 overexpression upregulated miR-17-3p expression. The miR-17-3p agomir mimicked the pro-proliferative and antiapoptotic effects of METTL3 in
hypoxia-exposed cells or rats with MI, while the miR-17-3p
antagomir blocked these effects. Additionally, pretreatment with the
RNA-binding protein DGCR8 also hampered the protective role of METTL3 in
hypoxia-exposed cells. Overall, the current study indicated that METTL3 could improve cardiomyocyte proliferation and subsequently ameliorate MI in rats by upregulating proliferation-related miR-17-3p in a DGCR8-dependent
pri-miRNA-processing manner.