BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes.

Life Science Alliance
Hyoung K KimJin Han

Abstract

Diabetic cardiomyopathy (DCM) is a major cause of mortality/morbidity in diabetes mellitus patients. Although tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous cardiovascular target, its effect on myocardial cells and mitochondria in DCM and the underlying mechanisms remain unknown. Here, we determined the involvement of BH4 deficiency in DCM and the therapeutic potential of BH4 supplementation in a rodent DCM model. We observed a decreased BH4:total biopterin ratio in heart and mitochondria accompanied by cardiac remodeling, lower cardiac contractility, and mitochondrial dysfunction. Prolonged BH4 supplementation improved cardiac function, corrected morphological abnormalities in cardiac muscle, and increased mitochondrial activity. Proteomics analysis revealed oxidative phosphorylation (OXPHOS) as the BH4-targeted biological pathway in diabetic hearts as well as BH4-mediated rescue of down-regulated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) signaling as a key modulator of OXPHOS and mitochondrial biogenesis. Mechanistically, BH4 bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and activated downstream AMP-activated protein kinase/cAMP response element bind...Continue Reading

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Citations

Jul 27, 2021·Frontiers in Cell and Developmental Biology·Jia-Yue DuanLing-Qing Yuan

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Methods Mentioned

BETA
OLETF
surface plasmon resonance
confocal microscopy
transfection

Software Mentioned

GraphPad Prism
GraphPad
STRING
Cytoscape

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