Omentin-1 Promotes Cardiomyocyte Maturation By Antagonism BMP7

Objectives:Cardiomyocyte maturation is a process in which fetal immature cardiomyocytes undergo a series of structural,functional and metabolic transformations to develop into adult mature cardiomyocytes.Cardiomyocyte maturation is closely related to the pathogenesis of cardiomyopathy,the progression of heart failure,and the clinical application of pluripotent stem cells derived cardiomyocytes.However,the regulator and regulation mechanisms of cardiomyocyte maturation have not been fully elucidated.Therefore,in this study,we aimed to 1)investigate the role of adipokines omentin-1 in cardiomyocyte maturation.2)explore the mechanism of adipokines omentin-1 in regulating cardiomyocyte maturation.3)explore more cardiomyocyte maturation regulators and regulatory mechanisms.Methods:The cardiac function of omentin-1 knockout(KO)mice was dynamically observed by echocardiography during postnatal heart development.Transcriptome sequencing(RNA-seq)was used to explore the mechanism of omentin-1 regulating postnatal cardiac function.The effects of omentin-1 on the cardiomyocyte’s mature phenotypes were observed by isolating primary cardiomyocytes,human embryonic stem cell derived cardiomyocyte,neonatal mice,and mice suffering apical resection surgery.Through protein docking,molecular simulation,coimmunoprecipitation,Western blot and other technologies,the downstream regulation mechanism and pathway of omentin-1 were elucidated.RNA-seq and protein profiling of heart tissue of neonatal and adult mice were performed to screen novel regulators and mechanisms for cardiomyocyte maturation.Results:The expression of omentin-1 increases during postnatal development in mice.Knocking out omentin-1 in mice leads to progressive cardiac dysfunction during postnatal heart development,and the heart gets enlargement,ventricular wall thinning,and heart failure in adulthood.RNA-seq and phenotypic analysis revealed that the proliferation of cardiomyocytes increases within energy metabolism decreases in Omentin-1 KO mice.Through in vitro and in vivo experiments,it was found that exogenous administration of omentin-1 promotes cardiomyocyte proliferation arrest and enhances cardiomyocyte energy metabolism.Molecular docking and simulation found that omentin-1 promotes cardiomyocyte maturation by antagonizing the extracellular protein BMP7.And omentin-1 mediates cardiomyocyte proliferation by the downstream pathway of BMP7/Smad1/YAP.And through both BMP7/Smad1/YAP and BMP7/p38 MAPK pathways,omentin-1 regulates cardiomyocyte metabolism maturation.Transcriptomic and proteomic analyses of neonatal and adult mouse hearts identified a total of 254 factors that both altered at transcriptional and protein levels.The functional analysis found that m RNA processing and energy metabolism pathways were novel mechanisms for cardiomyocyte maturation.Moreover,the regulator 2-oxoglutarate dehydrogenase multienzyme(Odghl)dramatic increased in adult heart and interfering Odghl expression in cardiomyocyte reduced energy metabolism.Conclusions:1)Omentin-1 is a novel cardiomyocyte maturation regulator that promotes cell cycle arrest and enhances energy metabolism by antagonizing BMP7.2)Proteogenomics integrating analysis revealed that m RNA processing and energy metabolism were two regulatory mechanisms.3)Odghl is a newly discovered potential regulator for cardiomyocyte metabolic maturation.Taken together,this paper through animal,cellular and molecular experiments revealed that omentin-1 is a newly discovered cardiomyocyte maturation regulator,which promotes the proliferation arrest and metabolic maturation of cardiomyocytes.Through the combined analysis of neonatal and adult cardiac transcription and proteomics,it was found that m RNA processing and energy metabolism are important regulatory mechanisms of postnatal myocardial maturation,and Odghl is a potential regulator of myocardial maturation,providing more evidence and ideas for the study of postnatal myocardial maturation regulators and regulatory mechanisms.