Elevated MCU Expression by CaMKII delta B Limits Pathological Cardiac Remodeling

Article

关键词: DEPENDENT PROTEIN-KINASE;    NUCLEAR-LOCALIZATION SIGNAL;    MITOCHONDRIAL CA2+;    HEART-FAILURE;    DILATED CARDIOMYOPATHY;    FLUORESCENT PROTEINS;    MICE LACKING;    ACTIVATION;    UNIPORTER;    PHOSPHORYLATION;   

DOI  :  10.1161/CIRCULATIONAHA.121.055841

来源: SCIE

【 摘 要 】

Background: Calcium (Ca2+) is a key regulator of energy metabolism. Impaired Ca2+ homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca2+ uniporter (MCU) in chronic stress-induced pathological cardiac remodeling. Methods: MCU knockout or transgenic mice were infused with isoproterenol (ISO, 10 mg/kg/day, 4 weeks). Cardiac hypertrophy and remodeling were evaluated by echocardiography and histology. Primary cultured rodent adult cardiomyocytes were treated with ISO (1 nmol/L, 48 hours). Intracellular Ca2+ handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro. Results: Chronic administration of the beta-adrenergic receptor (beta-AR) agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca2+ concentrations, in vivo and in vitro. ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. Interestingly, ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout (KO) mice. Cardiomyocytes from KO mice or mice overexpressing a dominant negative MCU exhibited defective intracellular Ca2+ handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca2+ homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca2+/calmodulin kinase II delta B (CaMKII delta B) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKII delta B phosphorylated cAMP-response element binding protein (CREB), which bound the MCU promotor to enhance MCU gene transcription. Conclusions: The beta-AR/CaMKII delta B/CREB pathway upregulates MCU gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca2+ homeostasis and cardiomyocyte viability.

【 授权许可】

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