Tetrahydrobiopterin enhances mitochondrial biogenesis and cardiac contractility via stimulation of PGC1α signaling

Kim, Hyoung Kyu; Jeon, Jouhyun; Song, In-Sung; Heo, Hae Jin; Jeong, Sang Hoon; Long, Lê Thanh; Thu, Vũ Thị; Ko, Tae Hee; Kim, Min; Kim, Nari; Lee, Sung Ryul; Yang, Jun; Kang, Mi Seon; Ahn, Jung‐Mo; Cho, Je‐Yoel; Ko, Kyung Soo; Rhee, Byoung Doo; Nilius, Bernd; Ha, Nam‐Chul; Shimizu, Ippei; Minamino, Tohru; Cho, Kyoung Im; Park, Young Shik; Kim, Sanguk; Han, Jin

doi:10.1016/j.bbadis.2019.07.018

Cited by 12 publications

(14 citation statements)

References 40 publications

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“…We recently reported the beneficial effects of BH4 in mitochondria in Spr −/− mice (Kim et al, 2019). BH4-deficient animals Figure 6.…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported the beneficial effects of BH4 in mitochondria in Spr −/− mice ( Kim et al, 2019 ). BH4-deficient animals display severe cardiac dysfunction accompanied by mitochondrial defects, and we found that BH4 regulates Pgc1a transcription, downstream mitochondrial biogenesis, and the OXPHOS system ( Kim et al, 2019 ). In this study, we demonstrated that both DCM condition and BH4 deficiency reduced activation of AMPK and CREB, both of which can induce the expression of Pgc1a and regulators of mitochondrial biogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…3-wk-old Spr −/− mice were treated with either BH4 (20 mg/kg/day via i.p. injection) or vehicle for 4 wk, with same-age littermate Spr +/+ mice used as controls (Kim et al, 2019).…”

Section: Methodsmentioning

confidence: 99%

“…The BH4-eNOS uncoupling is associated with vascular disease, hypertrophic cardiac remodeling, and ischemia-reperfusion injury (Kim et al, 2010). We previously demonstrated that BH4 deficiency increases ROS generation and mitochondrial dysfunction independent of NO (Kim et al, 2007) and that a mouse model of BH4 deficiency (sepiapterin reductase-knockout [Spr −/− ] mice) displayed severe functional impairment in the heart and mitochondria, which was rescued by exogenous BH4 supplementation (Kim et al, 2019). Moreover, a recent study suggested that BH4 protects against hypertrophic heart disease independent of myocardial nitric oxide synthase (NOS) coupling (Hashimoto et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…This study aimed to determine the involvement of BH4 deficiency in DCM and the ability of BH4 supplementation to restore mitochondrial and heart function during late-stage DCM in rat models (Otsuka Long–Evans Tokushima Fatty [OLETF] rats [ Hayashi et al, 2003 ], db/db mice [ Verma et al, 2018 ], and Spr −/− mice Kim et al, 2019 ]).…”

Section: Introductionmentioning

confidence: 99%

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

Kim

Song

et al. 2020

Life Sci. Alliance

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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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“…We recently reported the beneficial effects of BH4 in mitochondria in Spr −/− mice (Kim et al, 2019). BH4-deficient animals Figure 6.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…3-wk-old Spr −/− mice were treated with either BH4 (20 mg/kg/day via i.p. injection) or vehicle for 4 wk, with same-age littermate Spr +/+ mice used as controls (Kim et al, 2019).…”

Section: Methodsmentioning

confidence: 99%