Increasing tetrahydrobiopterin in cardiomyocytes adversely affects cardiac redox state and mitochondrial function independently of changes in NO production. Free Radic Biol Med 2016 Apr;93:1-11
Date
01/31/2016Pubmed ID
26826575Pubmed Central ID
PMC5498285DOI
10.1016/j.freeradbiomed.2016.01.019Scopus ID
2-s2.0-84959375364 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Tetrahydrobiopterin (BH4) represents a potential strategy for the treatment of cardiac remodeling, fibrosis and/or diastolic dysfunction. The effects of oral treatment with BH4 (Sapropterin™ or Kuvan™) are however dose-limiting with high dose negating functional improvements. Cardiomyocyte-specific overexpression of GTP cyclohydrolase I (mGCH) increases BH4 several-fold in the heart. Using this model, we aimed to establish the cardiomyocyte-specific responses to high levels of BH4. Quantification of BH4 and BH2 in mGCH transgenic hearts showed age-based variations in BH4:BH2 ratios. Hearts of mice (<6 months) have lower BH4:BH2 ratios than hearts of older mice while both GTPCH activity and tissue ascorbate levels were higher in hearts of young than older mice. No evident changes in nitric oxide (NO) production assessed by nitrite and endogenous iron-nitrosyl complexes were detected in any of the age groups. Increased BH4 production in cardiomyocytes resulted in a significant loss of mitochondrial function. Diminished oxygen consumption and reserve capacity was verified in mitochondria isolated from hearts of 12-month old compared to 3-month old mice, even though at 12 months an improved BH4:BH2 ratio is established. Accumulation of 4-hydroxynonenal (4-HNE) and decreased glutathione levels were found in the mGCH hearts and isolated mitochondria. Taken together, our results indicate that the ratio of BH4:BH2 does not predict changes in neither NO levels nor cellular redox state in the heart. The BH4 oxidation essentially limits the capacity of cardiomyocytes to reduce oxidant stress. Cardiomyocyte with chronically high levels of BH4 show a significant decline in redox state and mitochondrial function.
Author List
Sethumadhavan S, Whitsett J, Bennett B, Ionova IA, Pieper GM, Vasquez-Vivar JAuthors
Brian Bennett D.Phil. Professor and Chair in the Physics department at Marquette UniversityJeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AldehydesAnimals
Dose-Response Relationship, Drug
Endothelium, Vascular
GTP Cyclohydrolase
Glutathione
Humans
Mice
Mice, Transgenic
Mitochondria
Myocytes, Cardiac
Nitric Oxide
Oxidation-Reduction
Oxidative Stress
Oxygen Consumption
Superoxides