Silencing of METTL3 attenuates cardiac fibrosis induced by myocardial infarction via inhibiting the activation of cardiac fibroblasts

Abstract

Cardiac fibrosis is characterized by the activation of cardiac fibroblasts and accumulation of extracellular matrix. METTL3, a component of methyltransferase complex, participates in multiple biological processes associated with mammalian development and disease progression. However, the role of METTL3 in cardiac fibrosis is still unknown. We performed fibroblasts activation with TGF-β1 (20 ng/mL) in vitro and established in vivo mouse models with lentivirus to assess the effects of METTL3 on cardiac fibroblasts proliferation and collagen formation. Methylated RNA immunoprecipitation (MeRIP) was used to define the potential fibrosis-regulated gene. The expression level of METTL3 was increased in cardiac fibrotic tissue of mice with chronic myocardial infarction and cultured cardiac fibroblats (CFs) treated with TGF-β1. Enforced expression of METTL3 promoted proliferation and fibroblastto-myofibroblast transition and collagens accumulation, while silence of METTL3 did the opposite. Silence of METTL3 by lentivirus carrying METTL3 siRNA markedly alleviated cardiac fibrosis in MI mice. Transcriptome and N6-methyladenosine (m 6 A) profiling analyses revealed that the expression and m 6 A level of collagen-related genes were altered after silence of METTL3. METTL3-mediated m 6 A modification is critical for the development of cardiac fibrosis, providing a molecular target for manipulating fibrosis and the associated cardiac diseases.

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

“…However, silencing METTL3 was also reported to attenuate MIinduced cardiac fibrosis [35] and increase the protective autophagic flux in I/R-exposed mouse hearts in vivo [36], which seems to be different from our findings. Notably, in addition to the different modeling methods in the later study [18], the in vivo sampling time window in both studies was 4 weeks after surgery.…”

METTL3 Intensifies the Progress of Oral Squamous Cell Carcinoma via Modulating the m6A Amount of PRMT5 and PD-L1

“…METTL3 is one of the most important proteins in the m6A methyltransferase complex, which is mainly responsible for the m6A modification of RNA molecules on N6-methyladenine [ 22 , 23 ]. m6A is a widely existing base modification behavior on mRNA, which can maintain mRNA stability [ 30 ].…”

“…METTL3 is one of the most important proteins in the m6A methyltransferase complex, which is mainly responsible for catalyzing the m6A modification of RNA molecules on N6-methyladenine [ 22 , 23 ]. The deletion or abnormal expression of METTL3 will affect the level of m6A of intracellular RNA and then affect the degradation and translation of mRNA and the generation of microRNA, which may lead to the occurrence of human diseases [ 24 , 25 ].…”

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

“…Although the study of RNA modifications, epitranscriptomics remains in its infancy, methodological breakthroughs of the last decade have enabled identification of these modifications with such accuracy that their large-scale screening is rational [ 117 , 118 , 119 , 120 , 121 , 143 ]. Encouragingly, research findings suggest both m 6 A and A-to-I to act as contributors or even potential initiators and drivers for several cardiovascular physiological and pathological processes including cardiogenesis, angiogenesis, hypertension, hypertrophy, atherosclerosis, ischemia, ischemia-reperfusion, fibrosis, HF, congenital heart disease, stroke, aneurysms, as well as cardiac repair and regeneration [ 25 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 51 , 52 , 53 , 54 , 55 , 56 ]. Remarkably, the first indication for coronary atherosclerosis to be reflected in the m 6 A content of mRNAs and long non-coding RNAs of peripheral mononuclear cells with suggested involvement in its pathophysiology has just recently been reported [ 151 ].…”

“…Silencing or overexpression of enzymes controlling m 6 A abundance has revealed the role of m 6 A in driving immune reactivity, proliferation, apoptosis, and many intracellular processes including mRNA splicing, translation, and degradation [ 20 , 26 ], as well as miRNA biogenesis [ 27 ]. Moreover, reports from diverse fields of research [ 28 , 29 , 30 , 31 ], and in an array of cardiovascular pathologies [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], provide evidence of m 6 A as a master post-transcriptional regulator.…”