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Alliance"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:p>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-\u03b3 coactivator 1-\u03b1 (PGC-1\u03b1) 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-1\u03b1 signaling to rescue mitochondrial and cardiac dysfunction in DCM. These results suggest BH4 as a novel endogenous activator of CaMKK2.<\/jats:p>","DOI":"10.26508\/lsa.201900619","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T18:22:51Z","timestamp":1595442171000},"page":"e201900619","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes"],"prefix":"10.26508","volume":"3","author":[{"given":"Hyoung Kyu","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Physiology, BK21 Plus Project Team, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Hee","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Physiology, BK21 Plus Project Team, College of Medicine, 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