Study On The Role And Mechanism Of Transcription Factor HEY2 In Regulating Cardiac Energy Homeostasis

The heart is the earliest organ formed during embryonic development,and its physiological function accompanies humans throughout their lives.However,the morbidity and mortality of cardiovascular disease(CVD)are on the rise,and identifying the underlying pathogenic mechanisms and reliable drug targets has become an urgent task in scientific research.In adult hearts,differentiated myocardial cells contain a large number of mitochondria and powerful energy production capacity consistent with high energy demand.ATP produced by mitochondria is the main source of energy for various physiological activities in the heart and plays an important role in cardiac energy metabolism.Abnormal mitochondrial function can result in decreased ATP production and increased reactive oxygen species(ROS),disrupting the energy homeostasis of myocardial cells.The transcriptional repressor HEY2 is a key regulator in cardiovascular development,but its cellular and molecular mechanisms involved in regulating cardiac energy homeostasis remain unclear.In this study,by constructing a cell model of neonatal rat ventricular myocytes(NRVMs)overexpressing Hey2 and an adult mouse model with cardiac-specific Hey2 knockout,we comprehensively analyzed the effects and mechanisms of Hey2 signaling pathway gain and loss function on myocardial cells and the heart.Firstly,In vitro experiments demonstrating Hey2 overexpression in NRVMs confirmed the abnormal phenotype resulting from Hey2 signaling pathway activation in myocardial cells: Hey2 signaling activation led to decreased NRVMs area,increased apoptosis,decreased mitochondrial membrane potential,and increased ROS.Secondly,the adult mouse model with cardiac-specific Hey2 knockout confirmed that Hey2 signaling loss caused enhanced cardiac function in mice,increased mitochondrial biogenesis and energy metabolism in myocardial cells,and protected the heart from doxorubicin(DOX)-induced mitochondrial damage and subsequent cardiac dysfunction.This study revealed the mechanism of Hey2 signaling pathway in regulating cardiac energy homeostasis: HEY2 binds and inhibits the expression of key genes Ppargc1 a,Esrra,and Nrf1 involved in mitochondrial energy regulation,resulting in decreased mitochondrial energy metabolism.In summary,we discovered the pivotal role of Hey2 signaling pathway in maintaining cardiac homeostasis and its molecular mechanism of regulation through in vitro and in vivo models.The findings of this study provide a valuable contribution to the understanding of cardiac energy homeostasis and metabolic disorders,indicating that Hey2 signaling is not only important during development but also plays a critical role in energy metabolism.This achievement provides new insights for exploring the pathogenic mechanisms of heart disease and potential strategies for discovering clinical drug targets.