Myocardial ischemia results in tetrahydrobiopterin (BH 4 ) oxidation with impaired endothelial function ameliorated by BH 4
Open accessAbstract
Coronary vasodilation is impaired in the postischemic heart with a loss of endothelial nitric oxide synthase (eNOS) activity, but the mechanisms underlying ischemia-induced eNOS dysfunction are not understood. For nitric oxide (NO) synthesis, eNOS requires the redox-sensitive cofactor tetrahydrobiopterin (BH 4 ); however, the role of BH 4 in ischemia-induced endothelial dysfunction remains unknown. Therefore, isolated rat hearts were subjected to varying durations of ischemia, and the alterations in NOS-dependent vasodilation were measured and correlated with assays of eNOS activity and cardiac BH 4 concentrations. Ischemia time-dependently decreased cardiac BH 4 content with 85, 95, or 97% irreversible degradation after 30, 45, or 60 min of ischemia, respectively. Paralleling the decreases in BH 4 , reductions of eNOS activity were seen of 58, 86, or 92%, and NOS-derived superoxide production was greatly increased. Addition of 10 μM BH 4 enhanced eNOS activity in nonischemic hearts and partially restored activity after ischemia. It also suppressed NOS-derived superoxide production. Impaired coronary flow during postischemic reperfusion was improved by BH 4 infusion. Thus, BH 4 depletion contributes to postischemic eNOS dysfunction, and BH 4 treatment is effective in partial restoration of endothelium-dependent coronary flow. Supplementation of BH 4 may therefore be an important therapeutic approach to reverse endothelial dysfunction in postischemic tissues.
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The conversion of BH4 to BH2 in the setting of endothelial dysfunction has been widely reported.
“The conversion of BH4 to BH2 in the setting of endothelial dysfunction has been widely reported (192, 258, 550).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [258]
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- Authors
- Dumitrescu, C., Biondi, R., Xia, Y., Cardounel, A. J., Druhan, L. J., Ambrosio, G., & Zweier, J. L.
- Affiliations
- The Ohio State University (US)
- University of Perugia (IT)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-09-18
- Volume
- 104
- Issue
- 38
- Pages
- 15081-15086
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1986616
- OpenAlex
- W2007045655
- Cited by
- 192
- References
- 49
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 6 · 2019: 9 · 2018: 5 · 2017: 10 · 2016: 9 · 2015: 12 · 2014: 16 · 2013: 18 · 2012: 17
- FWCI
- 7.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-38324, HL-77575, R01HL063744, R01HL077575, HL 65608, P01HL065608, HL 63744, R01HL086965, R01HL038324, HL 86965)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- tetrahydrobiopterin, myocardial ischemia, endothelial nitric oxide synthase, endothelial dysfunction, coronary vasodilation, superoxide production, postischemic reperfusion, coronary blood flow, BH4 supplementation, isolated rat heart
- MeSH terms
- Animals, Biopterins, Endothelium, Vascular, Nitric Oxide, Oxidation-Reduction, Superoxides, Time Factors, Vasodilation, Myocardial Reperfusion Injury, Rats, Sprague-Dawley, Nitric Oxide Synthase, Rats, In Vitro Techniques
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