TY - JOUR T1 - BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900619 VL - 3 IS - 9 SP - e201900619 AU - Hyoung Kyu Kim AU - Tae Hee Ko AU - In-Sung Song AU - Yu Jeong Jeong AU - Hye Jin Heo AU - Seung Hun Jeong AU - Min Kim AU - Nam Mi Park AU - Dae Yun Seo AU - Pham Trong Kha AU - Sun-Woo Kim AU - Sung Ryul Lee AU - Sung Woo Cho AU - Jong Chul Won AU - Jae Boum Youm AU - Kyung Soo Ko AU - Byoung Doo Rhee AU - Nari Kim AU - Kyoung Im Cho AU - Ippei Shimizu AU - Tohru Minamino AU - Nam-Chul Ha AU - Young Shik Park AU - Bernd Nilius AU - Jin Han Y1 - 2020/09/01 UR - https://www.life-science-alliance.org/content/3/9/e201900619.abstract N2 - 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. ER -