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Tetrahydrobiopterin enhances mitochondrial biogenesis and cardiac contractility via stimulation of PGC1α signaling.
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2019 Nov 01; Vol. 1865 (11), pp. 165524. Date of Electronic Publication: 2019 Aug 03. - Publication Year :
- 2019
-
Abstract
- Tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous target in cardiovascular diseases. Although it is involved in cardiovascular metabolism and mitochondrial biology, its mechanisms of action are unclear. We investigated how BH4 regulates cardiovascular metabolism using an unbiased multiple proteomics approach with a sepiapterin reductase knock-out (Spr <superscript>-/-</superscript> ) mouse as a model of BH4 deficiency. Spr <superscript>-/-</superscript> mice exhibited a shortened life span, cardiac contractile dysfunction, and morphological changes. Multiple proteomics and systems-based data-integrative analyses showed that BH4 deficiency altered cardiac mitochondrial oxidative phosphorylation. Along with decreased transcription of major mitochondrial biogenesis regulatory genes, including Ppargc1a, Ppara, Esrra, and Tfam, Spr <superscript>-/-</superscript> mice exhibited lower mitochondrial mass and severe oxidative phosphorylation defects. Exogenous BH4 supplementation, but not nitric oxide supplementation or inhibition, rescued these cardiac and mitochondrial defects. BH4 supplementation also recovered mRNA and protein levels of PGC1α and its target proteins involved in mitochondrial biogenesis (mtTFA and ERRα), antioxidation (Prx3 and SOD2), and fatty acid utilization (CD36 and CPTI-M) in Spr <superscript>-/-</superscript> hearts. These results indicate that BH4-activated transcription of PGC1α regulates cardiac energy metabolism independently of nitric oxide and suggests that BH4 has therapeutic potential for cardiovascular diseases involving mitochondrial dysfunction.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Biopterins pharmacology
Male
Mice, Inbred C57BL
Mitochondria, Heart metabolism
Organelle Biogenesis
Signal Transduction drug effects
Biopterins analogs & derivatives
Cardiovascular Agents pharmacology
Mitochondria, Heart drug effects
Myocardial Contraction drug effects
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1865
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 31381993
- Full Text :
- https://doi.org/10.1016/j.bbadis.2019.07.018