Dilated cardiomyopathy(DCM)is the leading cause of heart transplantation.By microRNA(miRNA)array,a Kaposi’s sarcoma-associated herpes virus(KSHV)-encoded miRNA,kshv-miR-K12-1-5p,was detected in patients with DCM.The ...Dilated cardiomyopathy(DCM)is the leading cause of heart transplantation.By microRNA(miRNA)array,a Kaposi’s sarcoma-associated herpes virus(KSHV)-encoded miRNA,kshv-miR-K12-1-5p,was detected in patients with DCM.The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up.展开更多
Although numerous miRNAs have been discovered,their functions in the different subcellular organelles have remained obscure.In this study,we found that miR-665 was enriched in the nucleus of cardiomyocytes,and then in...Although numerous miRNAs have been discovered,their functions in the different subcellular organelles have remained obscure.In this study,we found that miR-665 was enriched in the nucleus of cardiomyocytes,and then investigated the underlying role of nuclear miR-665 in heart failure.RNA fluorescence in situ hybridization assays in human heart tissue sections and primary cardiomyocytes showed that miR-665 was localized in the nucleus of cardiomyocytes.Increased expression of nuclear miR-665 was observed not only in the cardiomyocytes isolated from the heart of mice treated in vivo by transverse aortic constriction(TAC),but also in phenylephrine(PE)-treated cultured cardiomyocytes in vitro.To further explore the role of miR-665 in heart failure,a type 9 recombinant adeno-associated virus(rAAV)system was employed to manipulate the expression of miR-665 in mice.Overexpression of miR-665 aggravated TAC-induced cardiac dysfunction,while down-expression of miR-665 showed opposite effects.Bioinformatic prediction and biological validation confirmed that the PTEN(phosphatase and tensin homolog)gene was one of the targets of miR-665 in the nucleus.Furthermore,restoring PTEN expression significantly eliminated the destructive effects of miR-665 over-expression in TAC-induced cardiac dysfunction.Our data showed that nuclear miR-665 aggravates heart failure via inhibiting PTEN expression,which provided a therapeutic approach for heart failure.展开更多
MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be co...MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be covered by the globe effects of it on the heart.In the current study,Langendorff system was applied to isolate card io myocytes(CMs)and cardiac fibroblasts(CFs)from transverse aortic constriction(TAC)-induced mice.Slight increase of miR-320 expression was observed in the whole heart tissue of TAC mice.Interestingly,miR-320 was significantly elevated in CMs but decreased in CFs from TAC mice at different time points.Then,recombinant adeno-associated virus 9 with cell-type-specific promoters were used to manipulate miR-320 expressions in vivo.Both in vitro and in vivo experiments showed the miR-320 overexpression in CMs exacerbated cardiac dysfunction,whereas overexpression of miR-320 in CFs alleviated cardiac fibrosis and hypertrophy.Mechanically,downstream signaling pathway analyses revealed that miR-320 might induce various effects via targeting PLEKHM3 and IFITM1 in CMs and CFs,respectively.Moreover,miR-320 mediated effects could be abolished by PLEKHM3 re-expression in CMs or IFITM1 re-expression in CFs.Interestingly,miR-320 treated CFs were able to indirectly affect CMs function,but not vice versa.Meanwhile,upstream signaling pathway analyses showed that miR-320 expression and decay rate were rigorously manipulated by Ago2,which was regulated by a cluster of cell-type-specific TFs distinctively expressed in CMs and CFs,respectively.Together,we demonstrated that miR-320 functioned differently in various cell types of the heart during the progression of HF.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(nos.81822002,82270363,91839302,81630010,81790624,31771264,31800973,and 82000387)National Key R&D Program of China(no.2017YFC0909400)the Natural Science Foundation of Hubei Province(no.2020CFA016).The funders had no role in study design,data collection and analysis,manuscript preparation,or decision to publish.
文摘Dilated cardiomyopathy(DCM)is the leading cause of heart transplantation.By microRNA(miRNA)array,a Kaposi’s sarcoma-associated herpes virus(KSHV)-encoded miRNA,kshv-miR-K12-1-5p,was detected in patients with DCM.The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up.
基金supported by grant from the National Natural Science Foundation of China(81822002,81630010,81790624,91839302,31771264 and 31800973)。
文摘Although numerous miRNAs have been discovered,their functions in the different subcellular organelles have remained obscure.In this study,we found that miR-665 was enriched in the nucleus of cardiomyocytes,and then investigated the underlying role of nuclear miR-665 in heart failure.RNA fluorescence in situ hybridization assays in human heart tissue sections and primary cardiomyocytes showed that miR-665 was localized in the nucleus of cardiomyocytes.Increased expression of nuclear miR-665 was observed not only in the cardiomyocytes isolated from the heart of mice treated in vivo by transverse aortic constriction(TAC),but also in phenylephrine(PE)-treated cultured cardiomyocytes in vitro.To further explore the role of miR-665 in heart failure,a type 9 recombinant adeno-associated virus(rAAV)system was employed to manipulate the expression of miR-665 in mice.Overexpression of miR-665 aggravated TAC-induced cardiac dysfunction,while down-expression of miR-665 showed opposite effects.Bioinformatic prediction and biological validation confirmed that the PTEN(phosphatase and tensin homolog)gene was one of the targets of miR-665 in the nucleus.Furthermore,restoring PTEN expression significantly eliminated the destructive effects of miR-665 over-expression in TAC-induced cardiac dysfunction.Our data showed that nuclear miR-665 aggravates heart failure via inhibiting PTEN expression,which provided a therapeutic approach for heart failure.
基金supported by grant from the National Natural Science Foundation of China(nos.81822002,31771264,31800973,and 81630010).
文摘MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be covered by the globe effects of it on the heart.In the current study,Langendorff system was applied to isolate card io myocytes(CMs)and cardiac fibroblasts(CFs)from transverse aortic constriction(TAC)-induced mice.Slight increase of miR-320 expression was observed in the whole heart tissue of TAC mice.Interestingly,miR-320 was significantly elevated in CMs but decreased in CFs from TAC mice at different time points.Then,recombinant adeno-associated virus 9 with cell-type-specific promoters were used to manipulate miR-320 expressions in vivo.Both in vitro and in vivo experiments showed the miR-320 overexpression in CMs exacerbated cardiac dysfunction,whereas overexpression of miR-320 in CFs alleviated cardiac fibrosis and hypertrophy.Mechanically,downstream signaling pathway analyses revealed that miR-320 might induce various effects via targeting PLEKHM3 and IFITM1 in CMs and CFs,respectively.Moreover,miR-320 mediated effects could be abolished by PLEKHM3 re-expression in CMs or IFITM1 re-expression in CFs.Interestingly,miR-320 treated CFs were able to indirectly affect CMs function,but not vice versa.Meanwhile,upstream signaling pathway analyses showed that miR-320 expression and decay rate were rigorously manipulated by Ago2,which was regulated by a cluster of cell-type-specific TFs distinctively expressed in CMs and CFs,respectively.Together,we demonstrated that miR-320 functioned differently in various cell types of the heart during the progression of HF.