The potential of circular RNAs(circRNAs)as biomarkers and therapeutic targets is becoming increasingly evident,yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored.Here,we investiga...The potential of circular RNAs(circRNAs)as biomarkers and therapeutic targets is becoming increasingly evident,yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored.Here,we investigated the function of circlGF1R and related mechanisms in cardiac regeneration.Through analysis of circRNA sequencing data from neonatal and adult cardiomyocytes,circRNAs associated with regeneration were identified.Our data showed that circlGFiR expression was high in neonatal hearts,decreased with postnatal maturation,and up-regulated after cardiac injury.The elevation was validated in patients diagnosed with acute myocardial infarction(Ml)within 1 week.In human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)and myocardial tissue from mice after apical resection and Ml,we observed that circlGF1R overexpression enhanced cardiomyocyte proliferation,reduced apoptosis,and mitigated cardiac dysfunction and fibrosis,while circlGF1R knockdown impeded endogenous cardiac renewal.Mechanistically,we identified circIGF1R binding proteins through circRNA precipitation followed by mass spectrometry.RNA pull-down Western blot and RNA immunoprecipitation demonstrated that circlGF1R directly interacted with DDX5 and augmented its protein level by suppressing ubiquitin-dependent degradation.This subsequently triggered theβ-catenin signaling pathway,leading to the transcriptional activation of cyclin D1 and c-Myc.The roles of circlGF1R and DDX5 in cardiac regeneration were further substantiated through site-directed mutagenesis and rescue experiments.In conclusion,our study highlights the pivotal role of circlGFiR in facilitating heart regeneration and repair after ischemic insults.The circlGF1R/DDX5/β-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair after Ml,offering promising avenues for the development of regenerative therapies.展开更多
基金support from various funding sources,including grants from Key Clinical Frontier Technology Project of Department of Science and Technology of Jiangsu Provincial(no.BE2022806)the National Natural Science Foundation of China Innovative Research Group Project(no.82121001)+1 种基金the National Natural Science Foundation of China(nos.82370344 and 82200382)the Scientific Research Innovation Projects of Graduate Students in Jiangsu Province(no.KYCX23_1940).
文摘The potential of circular RNAs(circRNAs)as biomarkers and therapeutic targets is becoming increasingly evident,yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored.Here,we investigated the function of circlGF1R and related mechanisms in cardiac regeneration.Through analysis of circRNA sequencing data from neonatal and adult cardiomyocytes,circRNAs associated with regeneration were identified.Our data showed that circlGFiR expression was high in neonatal hearts,decreased with postnatal maturation,and up-regulated after cardiac injury.The elevation was validated in patients diagnosed with acute myocardial infarction(Ml)within 1 week.In human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)and myocardial tissue from mice after apical resection and Ml,we observed that circlGF1R overexpression enhanced cardiomyocyte proliferation,reduced apoptosis,and mitigated cardiac dysfunction and fibrosis,while circlGF1R knockdown impeded endogenous cardiac renewal.Mechanistically,we identified circIGF1R binding proteins through circRNA precipitation followed by mass spectrometry.RNA pull-down Western blot and RNA immunoprecipitation demonstrated that circlGF1R directly interacted with DDX5 and augmented its protein level by suppressing ubiquitin-dependent degradation.This subsequently triggered theβ-catenin signaling pathway,leading to the transcriptional activation of cyclin D1 and c-Myc.The roles of circlGF1R and DDX5 in cardiac regeneration were further substantiated through site-directed mutagenesis and rescue experiments.In conclusion,our study highlights the pivotal role of circlGFiR in facilitating heart regeneration and repair after ischemic insults.The circlGF1R/DDX5/β-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair after Ml,offering promising avenues for the development of regenerative therapies.
