The prevalence of cardiovascular diseases(CVDs)has increased markedly as the world population has aged.Long non-coding RNAs(lncRNAs)have been reported as novel regulators in diverse pathophysiological conditions.Here,...The prevalence of cardiovascular diseases(CVDs)has increased markedly as the world population has aged.Long non-coding RNAs(lncRNAs)have been reported as novel regulators in diverse pathophysiological conditions.Here,we performed RNA sequencing(RNA-seq)and observed that the lncRNA Zeb1os1(zinc finger E-box binding homeobox 1,opposite strand 1),which is known as ZEB1-AS1(zinc finger E-box binding homeobox 1 antisense 1)in humans,was upregulated in the aged mice hearts,senescent cardiomyocytes,and human blood from elderly individuals.The human blood ZEB1-AS1 level was positively relevant to human age but negatively relevant to peak E to peak A(E/A).Silencing Zeb1os1 ameliorated diastolic dysfunction and cardiac senescence in aged mice.On the other hand,Zeb1os1 overexpression triggered cardiac dysfunction resembling that observed in aged mice.Mechanistically,we provide compelling evidence that Zeb1os1 interacts with the transient receptor potential mucolipin 1(TRPML1)for ubiquitination(UB)-mediated degradation.This process inhibits lysosomal Ca^(2+)efflux,impairing lysosome function.In addition,the functional domain of Zeb1os1,which contains the key nucleotides responsible for the pro-senescence property of full-length Zeb1os1 in cardiomyocytes.Together,these data suggest that Zeb1os1 is a potential target for ameliorating lysosomal dysfunction and aging-related cardiac impairment.展开更多
Brown adipose tissue(BAT),crucial for mammalian thermoregulation and energy metabolism,boasts a dense concentration of mitochondria.As a vital cellular organelle,mitochondria undergo substantial remodeling in cold env...Brown adipose tissue(BAT),crucial for mammalian thermoregulation and energy metabolism,boasts a dense concentration of mitochondria.As a vital cellular organelle,mitochondria undergo substantial remodeling in cold environments,playing a pivotal role in maintaining body temperature and energy balance[1].Mitochondrial dynamics.展开更多
Diabetic cardiomyopathy(DCM)is a medical condition characterized by cardiac remodeling and dysfunction in individuals with diabetes mellitus.Sarcoplasmic reticulum(SR)and mitochondrial Ca^(2+)overload in cardiomyocyte...Diabetic cardiomyopathy(DCM)is a medical condition characterized by cardiac remodeling and dysfunction in individuals with diabetes mellitus.Sarcoplasmic reticulum(SR)and mitochondrial Ca^(2+)overload in cardiomyocytes have been recognized as biological hallmarks in DCM;however,the specific factors underlying these abnormalities remain largely unknown.In this study,we aimed to investigate the role of a cardiac-specific long noncoding RNA,D830005E20Rik(Trdn-as),in DCM.Our results revealed the remarkably upregulation of Trdn-as in the hearts of the DCM mice and cardiomyocytes treated with high glucose(HG).Knocking down Trdn-as in cardiac tissues significantly improved cardiac dysfunction and remodeling in the DCM mice.Conversely,Trdn-as overexpression resulted in cardiac damage resembling that observed in the DCM mice.At the cellular level,Trdn-as induced Ca^(2+)overload in the SR and mitochondria,leading to mitochondrial dysfunction.RNA-seq and bioinformatics analyses identified calsequestrin 2(Casq2),a primary calcium-binding protein in the junctional SR,as a potential target of Trdn-as.Further investigations revealed that Trdn-as facilitated the recruitment of METTL14 to the Casq2 mRNA,thereby enhancing the m6A modification of Casq2.This modification increased the stability of Casq2 mRNA and subsequently led to increased protein expression.When Casq2 was knocked down,the promoting effects of Trdn-as on Ca^(2+)overload and mitochondrial damage were mitigated.These findings provide valuable insights into the pathogenesis of DCM and suggest Trdn-as as a potential therapeutic target for this condition.展开更多
基金funded by the National Natural Science Foundation of China(82273919,82270396,and U21A20339)the China Postdoctoral Science Foundation(2023T160176)。
文摘The prevalence of cardiovascular diseases(CVDs)has increased markedly as the world population has aged.Long non-coding RNAs(lncRNAs)have been reported as novel regulators in diverse pathophysiological conditions.Here,we performed RNA sequencing(RNA-seq)and observed that the lncRNA Zeb1os1(zinc finger E-box binding homeobox 1,opposite strand 1),which is known as ZEB1-AS1(zinc finger E-box binding homeobox 1 antisense 1)in humans,was upregulated in the aged mice hearts,senescent cardiomyocytes,and human blood from elderly individuals.The human blood ZEB1-AS1 level was positively relevant to human age but negatively relevant to peak E to peak A(E/A).Silencing Zeb1os1 ameliorated diastolic dysfunction and cardiac senescence in aged mice.On the other hand,Zeb1os1 overexpression triggered cardiac dysfunction resembling that observed in aged mice.Mechanistically,we provide compelling evidence that Zeb1os1 interacts with the transient receptor potential mucolipin 1(TRPML1)for ubiquitination(UB)-mediated degradation.This process inhibits lysosomal Ca^(2+)efflux,impairing lysosome function.In addition,the functional domain of Zeb1os1,which contains the key nucleotides responsible for the pro-senescence property of full-length Zeb1os1 in cardiomyocytes.Together,these data suggest that Zeb1os1 is a potential target for ameliorating lysosomal dysfunction and aging-related cardiac impairment.
基金This study was financially supported by the National Natural Science Foundation of China(No.82270396).
文摘Brown adipose tissue(BAT),crucial for mammalian thermoregulation and energy metabolism,boasts a dense concentration of mitochondria.As a vital cellular organelle,mitochondria undergo substantial remodeling in cold environments,playing a pivotal role in maintaining body temperature and energy balance[1].Mitochondrial dynamics.
基金supported by the National Natural Science Foundation of China(Nos.82273919,82270396,and U21A20339)the HMU Marshal Initiative Funding(No.HMUMIF-21022)the Science Foundation for the Excellent Youth Scholars of Heilongjiang Province(No.JJ2023YX0509).
文摘Diabetic cardiomyopathy(DCM)is a medical condition characterized by cardiac remodeling and dysfunction in individuals with diabetes mellitus.Sarcoplasmic reticulum(SR)and mitochondrial Ca^(2+)overload in cardiomyocytes have been recognized as biological hallmarks in DCM;however,the specific factors underlying these abnormalities remain largely unknown.In this study,we aimed to investigate the role of a cardiac-specific long noncoding RNA,D830005E20Rik(Trdn-as),in DCM.Our results revealed the remarkably upregulation of Trdn-as in the hearts of the DCM mice and cardiomyocytes treated with high glucose(HG).Knocking down Trdn-as in cardiac tissues significantly improved cardiac dysfunction and remodeling in the DCM mice.Conversely,Trdn-as overexpression resulted in cardiac damage resembling that observed in the DCM mice.At the cellular level,Trdn-as induced Ca^(2+)overload in the SR and mitochondria,leading to mitochondrial dysfunction.RNA-seq and bioinformatics analyses identified calsequestrin 2(Casq2),a primary calcium-binding protein in the junctional SR,as a potential target of Trdn-as.Further investigations revealed that Trdn-as facilitated the recruitment of METTL14 to the Casq2 mRNA,thereby enhancing the m6A modification of Casq2.This modification increased the stability of Casq2 mRNA and subsequently led to increased protein expression.When Casq2 was knocked down,the promoting effects of Trdn-as on Ca^(2+)overload and mitochondrial damage were mitigated.These findings provide valuable insights into the pathogenesis of DCM and suggest Trdn-as as a potential therapeutic target for this condition.
