Ischemic heart failure(HF)remains a leading cause of morbidity and mortality.Maintaining homeostasis of cardiac function and preventing cardiac remodeling deterioration are critical to halting HF progression.Methyltra...Ischemic heart failure(HF)remains a leading cause of morbidity and mortality.Maintaining homeostasis of cardiac function and preventing cardiac remodeling deterioration are critical to halting HF progression.Methyltransferase-like protein 13(Mettl13)has been shown to regulate protein translation efficiency by acting as a protein lysine methyltransferase,but its role in cardiac pathology remains unexplored.This study aims to characterize the roles and mechanisms of Mettl13 in cardiac contractile function and HF.We found that Mettl13 was downregulated in the failing hearts of mice post-myocardial infarction(MI)and in a cellular model of oxidative stress.Cardiomyocyte-specific overexpression of Mettl13 mediated by AAV9-Mettl13 attenuated cardiac contractile dysfunction and fibrosis in response to MI,while silencing of Mettl13 impaired cardiac function in normal mice.Moreover,Mettl13 overexpression abrogated the reduction in cell shortening,Ca^(2+)transient amplitude and SERCA2a protein levels in the cardiomyocytes of adult mice with MI.Conversely,knockdown of Mettl13 impaired the contractility of cardiomyocytes,and decreased Ca^(2+)transient amplitude and SERCA2a protein expression in vivo and in vitro.Mechanistically,Mettl13 impaired the stability of c-Cbl by inducing lysine methylation of c-Cbl,which in turn inhibited ubiquitination-dependent degradation of SERCA2a.Furthermore,the inhibitory effects of knocking down Mettl13 on SERCA2a protein expression and Ca^(2+)transients were partially rescued by silencing c-Cbl in H_(2)O_(2)-treated cardiomyocytes.In conclusion,our study uncovers a novel mechanism that involves the Mettl13/c-Cbl/SERCA2a axis in regulating cardiac contractile function and remodeling,and identifies Mettl13 as a novel therapeutic target for ischemic HF.展开更多
The coronavirus disease 2019(COVID-19)outbreak continues to spread rapidly around the world.By the end of 2020,there have been nearly 80 million confirmed cases and over 1.7 million deaths associated with COVID-19 glo...The coronavirus disease 2019(COVID-19)outbreak continues to spread rapidly around the world.By the end of 2020,there have been nearly 80 million confirmed cases and over 1.7 million deaths associated with COVID-19 globally(https://www.who.int/emergencies/diseases/novel-coronavirus-2019),with an estimated mortality rate of 0.03%–40%(Wiersinga et al.,2020).Noticeably,the COVID-19 is predicted to threaten millions of people throughout the world in the coming months and years.展开更多
基金supported by the National Natural Science Foundation of China (82273928,U21A20339)the Outstanding Youth Project of Natural Science Foundation of Heilongjiang Province (YQ2020H010)+2 种基金Youth Project of Scientific Research Institution of Heilongjiang Province (CZKYF2023-1-C047)CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-078)Harbin Medical University Youth Talents Start-up Funding (2019-YQ-03)。
文摘Ischemic heart failure(HF)remains a leading cause of morbidity and mortality.Maintaining homeostasis of cardiac function and preventing cardiac remodeling deterioration are critical to halting HF progression.Methyltransferase-like protein 13(Mettl13)has been shown to regulate protein translation efficiency by acting as a protein lysine methyltransferase,but its role in cardiac pathology remains unexplored.This study aims to characterize the roles and mechanisms of Mettl13 in cardiac contractile function and HF.We found that Mettl13 was downregulated in the failing hearts of mice post-myocardial infarction(MI)and in a cellular model of oxidative stress.Cardiomyocyte-specific overexpression of Mettl13 mediated by AAV9-Mettl13 attenuated cardiac contractile dysfunction and fibrosis in response to MI,while silencing of Mettl13 impaired cardiac function in normal mice.Moreover,Mettl13 overexpression abrogated the reduction in cell shortening,Ca^(2+)transient amplitude and SERCA2a protein levels in the cardiomyocytes of adult mice with MI.Conversely,knockdown of Mettl13 impaired the contractility of cardiomyocytes,and decreased Ca^(2+)transient amplitude and SERCA2a protein expression in vivo and in vitro.Mechanistically,Mettl13 impaired the stability of c-Cbl by inducing lysine methylation of c-Cbl,which in turn inhibited ubiquitination-dependent degradation of SERCA2a.Furthermore,the inhibitory effects of knocking down Mettl13 on SERCA2a protein expression and Ca^(2+)transients were partially rescued by silencing c-Cbl in H_(2)O_(2)-treated cardiomyocytes.In conclusion,our study uncovers a novel mechanism that involves the Mettl13/c-Cbl/SERCA2a axis in regulating cardiac contractile function and remodeling,and identifies Mettl13 as a novel therapeutic target for ischemic HF.
基金supported by the Youth Program of the National Natural Science Foundation of China(81700036)Major Scientific and Technological Innovation Projects of Chengdu Science and Technology Bureau(2020-YF08-00071-GX).
文摘The coronavirus disease 2019(COVID-19)outbreak continues to spread rapidly around the world.By the end of 2020,there have been nearly 80 million confirmed cases and over 1.7 million deaths associated with COVID-19 globally(https://www.who.int/emergencies/diseases/novel-coronavirus-2019),with an estimated mortality rate of 0.03%–40%(Wiersinga et al.,2020).Noticeably,the COVID-19 is predicted to threaten millions of people throughout the world in the coming months and years.
