Diabetic cardiomyopathy(DCM)is currently a progressive and nonstoppable complication in type 2 diabetic patients.Metabolic insults and insulin resistance are involved in its pathogenesis;however,the underlying mechani...Diabetic cardiomyopathy(DCM)is currently a progressive and nonstoppable complication in type 2 diabetic patients.Metabolic insults and insulin resistance are involved in its pathogenesis;however,the underlying mechanisms are still not clearly understood.Here we show that calcium dysregulation can be both a cause and a consequence of cardiac insulin resistance that leads to DCM.A western diet induces the development of DCM through at least three phases in mice,among which an early phase depends on impaired Thr^(484)-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a(SERCA2a)elicited by insulin resistance.Mutation of SERCA2a-Thr^(484) to a nonphosphorylatable alanine delays calcium re-uptake into the sarcoplasmic reticulum in the cardiomyocytes and decreases cardiac function at the baseline.Importantly,this mutation blunts the early phase of DCM,but has no effect on disease progression in the following phases.Interestingly,impairment of sarcoplasmic reticulum calcium re-uptake caused by the SERCA2a-Thr^(484) mutation inhibited processing of insulin receptor precursor through FURIN convertase,resulting in cardiac insulin resistance.Collectively,these data reveal a bidirectional relationship between insulin resistance and impairment of calcium homeostasis,which may underlie the early pathogenesis of DCM.Our findings have therapeutic implications for early intervention of DCM.展开更多
基金Thanks to the Ministry of Science and Technology of China(Grant Nos.2018YFA0801100 and 2021YFF0702100 to H.-Y.W.and S.C.)the National Natural Science Foundation of China(Grant Nos.32025019 and 31970719 to S.C.,82000349 to C.Q.,32000800 to M.L.,82000736 to Q.C.,and 31971067 to H.-Y.W.)+1 种基金the Science and Technology Foundation of Jiangsu Province of China(Grant Nos.BK20200315(Basic Research Program)to C.Q.and BK20190305(Basic Research Program)to Q.C.)the Fundamental Research Funds for the Central Universities(Grant Nos.021414380524 to S.C.,021414380508 to C.Q.,and 021414380505 to Q.C.),for financial support.
文摘Diabetic cardiomyopathy(DCM)is currently a progressive and nonstoppable complication in type 2 diabetic patients.Metabolic insults and insulin resistance are involved in its pathogenesis;however,the underlying mechanisms are still not clearly understood.Here we show that calcium dysregulation can be both a cause and a consequence of cardiac insulin resistance that leads to DCM.A western diet induces the development of DCM through at least three phases in mice,among which an early phase depends on impaired Thr^(484)-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a(SERCA2a)elicited by insulin resistance.Mutation of SERCA2a-Thr^(484) to a nonphosphorylatable alanine delays calcium re-uptake into the sarcoplasmic reticulum in the cardiomyocytes and decreases cardiac function at the baseline.Importantly,this mutation blunts the early phase of DCM,but has no effect on disease progression in the following phases.Interestingly,impairment of sarcoplasmic reticulum calcium re-uptake caused by the SERCA2a-Thr^(484) mutation inhibited processing of insulin receptor precursor through FURIN convertase,resulting in cardiac insulin resistance.Collectively,these data reveal a bidirectional relationship between insulin resistance and impairment of calcium homeostasis,which may underlie the early pathogenesis of DCM.Our findings have therapeutic implications for early intervention of DCM.
