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 fibroblast-to-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 (m6 A) profiling analyses revealed that the expression and m6 A level of collagen-related genes were altered after silence of METTL3. METTL3-mediated m6 A modification is critical for the development of cardiac fibrosis, providing a molecular target for manipulating fibrosis and the associated cardiac diseases.

• Authors: Tingting Li, Yuting Zhuang, Wanqi Yang, Yilin Xie, Wendi Shang, Shuang Su, Xue Dong, Jiaxu Wu, Wenmei Jiang, Yang Zhou, Ying Li, Xin Zhou, Mingyu Zhang, Yanjie Lu, Zhenwei Pan
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 35 Issue 2 Pg. e21162 (02 2021) ISSN: 1530-6860 [Electronic] United States
• PMID: 33150686 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Federation of American Societies for Experimental Biology.

Chemical References

• Transforming Growth Factor beta1
• Collagen
• Methyltransferases
• Mettl3 protein, mouse

Topics

• Animals
• Cell Proliferation (drug effects, genetics)
• Cells, Cultured
• Collagen (genetics, metabolism)
• Disease Models, Animal
• Fibrosis
• Gene Silencing
• Male
• Methyltransferases (genetics)
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (genetics, metabolism)
• Myocardium (pathology)
• Myofibroblasts (drug effects, metabolism)
• Signal Transduction (drug effects, genetics)
• Transcriptome
• Transfection
• Transforming Growth Factor beta1 (pharmacology)
• Up-Regulation (genetics)