Fibroblast-localized lncRNA CFIRL promotes cardiac fibrosis and dysfunction in dilated cardiomyopathy

CFIRL is a long noncoding RNA(lnc RNA),we previously identified as the most significantly upregulated lnc RNA in the failing hearts of patients with dilated cardiomyopathy(DCM).In this study,we determined the function of CFIRL and its role in DCM.Real-time polymerase chain reaction and in situ hybridization assays revealed that CFIRL was primarily localized in the nucleus of cardiac fibroblasts and robustly increased in failing hearts.Global knockdown or fibroblast-specific knockout of CFIRL attenuated transverse aortic constriction(TAC)-induced cardiac dysfunction and fibrosis in vivo.Overexpression of CFIRL in vitro promoted fibroblast proliferation and aggravated angiotensin II-induced differentiation to myofibroblasts.CFIRL knockdown attenuated these effects.Mechanistically,RNA pull-down assay and gene expression profiling revealed that CFIRL recruited ENO1,a newly identified noncanonical transcriptional factor,to activate IL-6transcription.IL-6 exerted a paracrine effect on cardiomyocytes to promote cardiac hypertrophy,which can be prevented by CFIRL knockdown.These findings uncover the critical role of CFIRL,a fibroblast-associated lnc RNA,in heart failure by facilitating crosstalk between fibroblasts and cardiomyocytes.CFIRL knockdown might be a potent strategy to prevent cardiac remodeling in heart failure,particularly in DCM.

Nuclear miR-665 aggravates heart failure via suppressing phosphatase and tensin homolog transcription

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.

Hyperglycemic memory in diabetic cardiomyopathy

Cardiovascular diseases account for approximately 80%of deaths among individuals with diabetes mellitus,with diabetic cardiomyopathy as the major diabetic cardiovascular complication.Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy,fibrosis,apoptosis,and other pathophysiological changes.Although glycemic control has long been at the center of diabetes therapy,multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes.This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level.This process is now referred to as hyperglycemic memory(HGM)phenomenon.We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.

The double face of miR-320:cardiomyocytes-derived miR-320 deteriorated while fibroblasts-derived miR-320 protected against heart failure induced by transverse aortic constriction

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.

MicroRNAs in cardiovascular diseases

Cardiovascular diseases(CVDs)are the leadingcauses of death and disability worldwide,despite thewide diversity of molecular targets identified and thedevelopment of therapeutic methods.MicroRNAs(miRNAs)are a class of small(about 22 nucleotides)non-codingRNAs(ncRNAs)that negatively regulate gene expressionat the post-transcriptional level in the cytoplasm and playcomplicated roles in different CVDs.While miRNA overexpression in one type of cell protects against heartdisease,it promotes cardiac dysfunction in another typeof cardiac cell.Moreover,recent studies have shown that,apart from cytosolic miRNAs,subcellular miRNAs suchas mitochondria-and nucleus-localized miRNAs aredysregulated in CVDs.However,the functional propertiesof cellular-and subcellular-localized miRNAs have notbeen well characterized.In this review article,by carefullyrevisiting animal-based miRNA studies in CVDs,we willaddress the regulation and functional properties ofmiRNAs in various CVDs.Specifically,the cell–cellcrosstalk and subcellular perspective of miRNAs arehighlighted.We will provide the background for attractivemolecular targets that might be useful in preventing theprogression of CVDs and heart failure(HF)as well asinsights for future studies.