Pathological cardiac hypertrophy contributes to the development of heart failure(HF).NOL1/NOP2/Sun domain family member 2(NSUN2)is implicated in pathophysiological processes of many diseases.However,the function and o...Pathological cardiac hypertrophy contributes to the development of heart failure(HF).NOL1/NOP2/Sun domain family member 2(NSUN2)is implicated in pathophysiological processes of many diseases.However,the function and operation of NSUN2 in cardiac hypertrophy and HF remain unclear.Here,we observed a significant increase in the levels of NSUN2 expression in both human hearts with HF and in mouse hearts with hypertrophy induced by transverse aortic constriction(TAC)and angiotensin II(Ang II)treatment.Cardiomyocyte-specific knockout of NSUN2 attenuated the reduced cardiac ejection fraction(EF)and fractional shortening(FS)and the increased heart weight to tibial length(HW/TL)upon either TAC or Ang II infusion.Conversely,cardiac-specific overexpression of NSUN2 resulted in cardiac remodeling as indicated by a prominent increase in hypertrophic growth and cardiac fibrosis and a robust decline in cardiac EF and FS.Mechanistically,NSUN2 induces 5-methylcytosine(m5C)modification of La-related protein 1(LARP1)to enhance its messenger RNA(mRNA)stability,which is mediated by Y-box binding protein 1(YBX1).Increased LARP1 further interacts with GATA binding protein 4(GATA4)mRNA and prevents its degradation.LARP1 silencing partially attenuates TAC and NSUN2 induced cardiac hypertrophy and HF.Collectively,this study provides a new insight into the central role of NSUN2 in cardiac hypertrophy,indicating that NSUN2 may serve as a novel therapeutic target for HF.展开更多
基金supported by grants from the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2024ZD0537909)the National Natural Science Foundation of China(82273928,82473919,82330011,82161148007)+2 种基金the Distinguished Young Scholars of Natural Science Foundation of Heilongjiang Province(JQ2024H002)the Chunyan Programme of Heilongjiang Province(CYQN2403)the CAMS Innovation Fund for Medical Sciences(CIFMS,2020-I2M-5-003).
文摘Pathological cardiac hypertrophy contributes to the development of heart failure(HF).NOL1/NOP2/Sun domain family member 2(NSUN2)is implicated in pathophysiological processes of many diseases.However,the function and operation of NSUN2 in cardiac hypertrophy and HF remain unclear.Here,we observed a significant increase in the levels of NSUN2 expression in both human hearts with HF and in mouse hearts with hypertrophy induced by transverse aortic constriction(TAC)and angiotensin II(Ang II)treatment.Cardiomyocyte-specific knockout of NSUN2 attenuated the reduced cardiac ejection fraction(EF)and fractional shortening(FS)and the increased heart weight to tibial length(HW/TL)upon either TAC or Ang II infusion.Conversely,cardiac-specific overexpression of NSUN2 resulted in cardiac remodeling as indicated by a prominent increase in hypertrophic growth and cardiac fibrosis and a robust decline in cardiac EF and FS.Mechanistically,NSUN2 induces 5-methylcytosine(m5C)modification of La-related protein 1(LARP1)to enhance its messenger RNA(mRNA)stability,which is mediated by Y-box binding protein 1(YBX1).Increased LARP1 further interacts with GATA binding protein 4(GATA4)mRNA and prevents its degradation.LARP1 silencing partially attenuates TAC and NSUN2 induced cardiac hypertrophy and HF.Collectively,this study provides a new insight into the central role of NSUN2 in cardiac hypertrophy,indicating that NSUN2 may serve as a novel therapeutic target for HF.
