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Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling
- Source :
- Circulation
- Publication Year :
- 2023
-
Abstract
- Background: Calcium (Ca 2+ ) is a key regulator of energy metabolism. Impaired Ca 2+ homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca 2+ uniporter (MCU) in chronic stress-induced pathological cardiac remodeling. Methods: MCU knockout or transgenic mice were infused with isoproterenol (ISO; 10 mg/kg per 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 Ca 2+ handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro. Results: Chronic administration of the β-adrenergic receptor agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca 2+ concentrations, in vivo and in vitro. ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. It is interesting that ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout mice. Cardiomyocytes from knockout mice or overexpressing a dominant negative MCU exhibited defective intracellular Ca 2+ handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca 2+ homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca 2+ /calmodulin kinase II δB (CaMKIIδB) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKIIδB phosphorylated CREB (cAMP-response element binding protein), which bound the Mcu promoter to enhance Mcu gene transcription. Conclusions: The β-adrenergic receptor/CaMKIIδB/CREB pathway upregulates Mcu gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca 2+ homeostasis and cardiomyocyte viability.
Details
- ISSN :
- 15244539
- Volume :
- 145
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Circulation
- Accession number :
- edsair.doi.dedup.....3bebdd7c57bad95e3858c0a130c7dc06