Impaired SERCA2a phosphorylation causes diabetic cardiomyopathy through impinging on cardiac contractility and precursor protein processing
Impaired SERCA2a phosphorylation causes diabetic cardiomyopathy through impinging on cardiac contractility and precursor protein processing
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DOI：
10.1093/lifemeta/loac013
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Shuai Chen
中科院分区：
文献类型：
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作者：
Chao Quan;Sangsang Zhu;Ruizhen Wang;Jiamou Chen;Qiaoli Chen;Min Li;Shu Su;Qian Du;Minjun Liu;Hong-Yu Wang;Shuai Chen
Abstract 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 Thr484-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) elicited by insulin resistance. Mutation of SERCA2a-Thr484 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-Thr484 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.
