METTL3 improves cardiomyocyte proliferation upon myocardial infarction via upregulating miR-17-3p in a DGCR8-dependent manner

缺氧(环境) 下调和上调 细胞凋亡 基因沉默 细胞生物学 拮抗剂 心肌梗塞 细胞生长 心肌细胞 医学 内科学 生物 化学 有机化学 基因 生物化学 氧气 遗传学
作者
Kun Zhao,Chuanxi Yang,Jing Zhang,Wei Sun,Bin Zhou,Xiangqing Kong,Jing Shi
出处
期刊:Cell death discovery [Springer Nature]
卷期号:7 (1) 被引量:15
标识
DOI:10.1038/s41420-021-00688-6
摘要

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.
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