The Role of METTL3-Mediated N6-Methyladenosine (m6A) of JPH2 mRNA in Cyclophosphamide-Induced Cardiotoxicity

Frontiers in Cardiovascular Medicine

Fujian Wu¹  Chengwen Hang²  Xianjuan Lin²  Yangong Liu²  Shiqin Zhang²  Yuanxiu Song²  Min Zhu³  Ming Xu⁴  Zenghui Huang⁵  Feng Lan⁶ 

[1] Beijing Lab for Cardiovascular Precision Medicine, Anzhen Hospital, Capital Medical University, Beijing, China;Department of Cardiology and Institute of Vascular Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China;Department of Cardiology and Institute of Vascular Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China;State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Key Laboratory of Application of Pluripotent Stem Cells in Heart Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;Department of Cardiology and Institute of Vascular Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China;State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China;Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences (CAS), Beijing, China;State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Key Laboratory of Application of Pluripotent Stem Cells in Heart Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;Beijing Lab for Cardiovascular Precision Medicine, Anzhen Hospital, Capital Medical University, Beijing, China;

关键词: cyclophosphamide;    cardiotoxicity;    JPH2;    m6A methylation;    METTL3;    cardiomyocyte;   

DOI  :  10.3389/fcvm.2021.763469

来源: Frontiers

【 摘 要 】

Cyclophosphamide (CYP)-induced cardiotoxicity is a common side effect of cancer treatment. Although it has received significant attention, the related mechanisms of CYP-induced cardiotoxicity remain largely unknown. In this study, we used cell and animal models to investigate the effect of CYP on cardiomyocytes. Our data demonstrated that CYP-induced a prolonged cardiac QT interval and electromechanical coupling time courses accompanied by JPH2 downregulation. Moreover, N6-methyladenosine (m6A) methylation sequencing and RNA sequencing suggested that CYP induced cardiotoxicity by dysregulating calcium signaling. Importantly, our results demonstrated that CYP induced an increase in the m6A level of JPH2 mRNA by upregulating methyltransferases METTL3, leading to the reduction of JPH2 expression levels, as well as increased field potential duration and action potential duration in cardiomyocytes. Our results revealed a novel mechanism for m6A methylation-dependent regulation of JPH2, which provides new strategies for the treatment and prevention of CYP-induced cardiotoxicity.

【 授权许可】

CC BY