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BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes
- Source :
- Life Science Alliance
- Publication Year :
- 2020
- Publisher :
- LIFE SCIENCE ALLIANCE LLC, 2020.
-
Abstract
- This study reports that BH4 activates CaMKK2/PGC-1α; signaling pathway and has a therapeutic effect on diabetic cardiomyopathy.<br />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 binding protein/PGC-1α signaling to rescue mitochondrial and cardiac dysfunction in DCM. These results suggest BH4 as a novel endogenous activator of CaMKK2.
- Subjects :
- 0301 basic medicine
Male
Diabetic Cardiomyopathies
Health, Toxicology and Mutagenesis
Plant Science
030204 cardiovascular system & hematology
Mitochondrion
AMP-Activated Protein Kinases
Oxidative Phosphorylation
chemistry.chemical_compound
Mice
0302 clinical medicine
Diabetic cardiomyopathy
Myocytes, Cardiac
Cyclic AMP Response Element-Binding Protein
Research Articles
CAMKK2
Organelle Biogenesis
Ecology
Cardiac muscle
Heart
Mitochondria
medicine.anatomical_structure
cardiovascular system
Signal Transduction
Research Article
Cardiac function curve
medicine.medical_specialty
Biopterin
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Biochemistry, Genetics and Molecular Biology (miscellaneous)
03 medical and health sciences
Internal medicine
medicine
Diabetes Mellitus
Animals
Rats, Long-Evans
Protein kinase A
business.industry
Myocardium
medicine.disease
Myocardial Contraction
Rats
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
Mitochondrial biogenesis
chemistry
business
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Life Science Alliance
- Accession number :
- edsair.doi.dedup.....cd30533f9058eb00fce6f36f9d035672