ArticleLife science alliance2020
BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes.
Article in Life science alliance, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 16 citations in OpenAlex.
- Reversing diastolic dysfunction in diabetes: a mitochondrial quality control-centric pharmacological approach.Acta diabetologica · 2026Review
- Loss of p300/CBP-associated factor aggravates cardiac remodeling via regulation of CAMKK2 acetylation.Experimental & molecular medicine · 2026Article
- Sacubitril/Valsartan Ameliorates Inflammation and Oxidative Stress in Hypertensive Heart Disease by Upregulating CAMKK2 Protein and Modulating the AMPK/AKT/GSK-3β Axis.The Kaohsiung journal of medical sciences · 2026Article
- Dapagliflozin improves diabetic kidney disease by inhibiting ferroptosis through β-hydroxybutyrate production.Renal failure · 2025Article
- Identification of key autophagy-related genes in arrhythmogenic right ventricular cardiomyopathy through gene expression profiling.Medicine · 2025Article
- Peroxisome proliferator‑activated receptor γ coactivator‑1α in heart disease (Review).Molecular medicine reports · 2025Review
- Diabetes cardiomyopathy: targeted regulation of mitochondrial dysfunction and therapeutic potential of plant secondary metabolites.Frontiers in pharmacology · 2024Review
- Novel insights into the role of mitochondria in diabetic cardiomyopathy: molecular mechanisms and potential treatments.Cell stress & chaperones · 2023Review
- Targeting ferroptosis: a novel insight against myocardial infarction and ischemia-reperfusion injuries.Apoptosis : an international journal on programmed cell death · 2023Review
- Calcium Signalling in Heart and Vessels: Role of Calmodulin and Downstream Calmodulin-Dependent Protein Kinases.International journal of molecular sciences · 2022Review
- Tetrahydrobiopterin (BHBiomedicines · 2022Article
- The Role of Mitochondrial Biogenesis Dysfunction in Diabetic Cardiomyopathy.Biomolecules & therapeutics · 2022Review
- Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?Frontiers in cell and developmental biology · 2021Review
Corrections and comments
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Authors and funding
25 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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 binding protein/PGC-1α signaling to rescue mitochondrial and cardiac dysfunction in DCM. These results suggest BH4 as a novel endogenous activator of CaMKK2.
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