Objective:Myocardial ischemia-reperfusion injury(MIRI)is one of the leading causes of death from cardiovascular disease in humans,especially in individuals exposed to cold environments.Long non-coding RNAs(lncRNAs)reg...Objective:Myocardial ischemia-reperfusion injury(MIRI)is one of the leading causes of death from cardiovascular disease in humans,especially in individuals exposed to cold environments.Long non-coding RNAs(lncRNAs)regulate MIRI through multiple mechanisms.This study explored the regulatory effect of lncRNA-AK138945 on myocardial ischemia-reperfusion injury and its mechanism.Methods:In vivo,8-to 12-weeks-old C57BL/6 male mice underwent ligation of the left anterior descending coronary artery for 50 minutes followed by reperfusion for 48 hours.In vitro,the primary cultured neonatal mouse ventricular cardiomyocytes(NMVCs)were treated with 100μmol/L hydrogen peroxide(H_(2)O_(2)).The knockdown of lncRNA-AK138945 was evaluated to detect cardiomyocyte apoptosis,and a glucose-regulated,endoplasmic reticulum stress-related protein 94(GRP94)inhibitor was used to detect myocardial injury.Results:We found that the expression level of lncRNA-AK138945 was reduced in MIRI mouse heart tissue and H2O2-treated cardiomyocytes.Moreover,the proportion of apoptosis in cardiomyocytes increased after lncRNA-AK138945 was silenced.The expression level of Bcl2 protein was decreased,and the expression level of Bad,Caspase 9 and Caspase 3 protein was increased.Our further study found that miR-1a-3p is a direct target of lncRNA-AK138945,after lncRNA-AK138945 was silenced in cardiomyocytes,the expression level of miR-1a-3p was increased while the expression level of its downstream protein GRP94 was decreased.Interestingly,treatment with a GRP94 inhibitor(PU-WS13)intensified H2O2-induced cardiomyocyte apoptosis.After overexpression of FOXO3,the expression levels of lncRNA-AK138945 and GRP94 were increased,while the expression levels of miR-1a-3p were decreased.Conclusion:LncRNA-AK138945 inhibits GRP94 expression by regulating miR-1a-3p,leading to cardiomyocyte apoptosis.The transcription factor Forkhead Box Protein O3(FOXO3)participates in cardiomyocyte apoptosis induced by endoplasmic reticulum stress through up-regulation of lncRNA-AK138945.展开更多
Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death.However,the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear.Here,we identified that the expressio...Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death.However,the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear.Here,we identified that the expression of sterile alpha and TIR motif containing 1(SARM1),was increased significantly in the ischemic cardiomyopathy patients,dilated cardiomyopathy patients(GSE116250)and fibrotic heart tissues of mice.Additionally,inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction(MI)mice.Moreover,SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function.Mechanically,elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1.Notably,by using the Click-iT reaction,we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1,thereby accelerating the fibrosis process.Based on the fibrosis-promoting effect of SARM1,we screened several drugs with anti-myocardial fibrosis activity.In conclusion,we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis.Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis.The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.展开更多
基金This work was supported in part by the National Natural Science Foundation of China(82370417,81970320,82270273)the Certificate of China Postdoctoral Science Foundation Grant(2021M693826)+1 种基金the postdoctoral funding from Heilongjiang Province(21042230046)the Hai Yan Youth Fund from Harbin Medical University Cancer Hospital(JJQN2021-09).
文摘Objective:Myocardial ischemia-reperfusion injury(MIRI)is one of the leading causes of death from cardiovascular disease in humans,especially in individuals exposed to cold environments.Long non-coding RNAs(lncRNAs)regulate MIRI through multiple mechanisms.This study explored the regulatory effect of lncRNA-AK138945 on myocardial ischemia-reperfusion injury and its mechanism.Methods:In vivo,8-to 12-weeks-old C57BL/6 male mice underwent ligation of the left anterior descending coronary artery for 50 minutes followed by reperfusion for 48 hours.In vitro,the primary cultured neonatal mouse ventricular cardiomyocytes(NMVCs)were treated with 100μmol/L hydrogen peroxide(H_(2)O_(2)).The knockdown of lncRNA-AK138945 was evaluated to detect cardiomyocyte apoptosis,and a glucose-regulated,endoplasmic reticulum stress-related protein 94(GRP94)inhibitor was used to detect myocardial injury.Results:We found that the expression level of lncRNA-AK138945 was reduced in MIRI mouse heart tissue and H2O2-treated cardiomyocytes.Moreover,the proportion of apoptosis in cardiomyocytes increased after lncRNA-AK138945 was silenced.The expression level of Bcl2 protein was decreased,and the expression level of Bad,Caspase 9 and Caspase 3 protein was increased.Our further study found that miR-1a-3p is a direct target of lncRNA-AK138945,after lncRNA-AK138945 was silenced in cardiomyocytes,the expression level of miR-1a-3p was increased while the expression level of its downstream protein GRP94 was decreased.Interestingly,treatment with a GRP94 inhibitor(PU-WS13)intensified H2O2-induced cardiomyocyte apoptosis.After overexpression of FOXO3,the expression levels of lncRNA-AK138945 and GRP94 were increased,while the expression levels of miR-1a-3p were decreased.Conclusion:LncRNA-AK138945 inhibits GRP94 expression by regulating miR-1a-3p,leading to cardiomyocyte apoptosis.The transcription factor Forkhead Box Protein O3(FOXO3)participates in cardiomyocyte apoptosis induced by endoplasmic reticulum stress through up-regulation of lncRNA-AK138945.
基金supported by grants from the National Natural Science Foundation of China(82370417,82270273,82330011,and U21A20339)Heilongjiang Province National Science Fund for Distinguished Young Scholars(JQ2024H001,China)CAMS Innovation Fund for Medical Sciences(2020-I2M-5-003,China)。
文摘Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death.However,the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear.Here,we identified that the expression of sterile alpha and TIR motif containing 1(SARM1),was increased significantly in the ischemic cardiomyopathy patients,dilated cardiomyopathy patients(GSE116250)and fibrotic heart tissues of mice.Additionally,inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction(MI)mice.Moreover,SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function.Mechanically,elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1.Notably,by using the Click-iT reaction,we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1,thereby accelerating the fibrosis process.Based on the fibrosis-promoting effect of SARM1,we screened several drugs with anti-myocardial fibrosis activity.In conclusion,we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis.Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis.The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.
