| Myocardial ischemia results in tetrahydrobiopterin (BH4) oxidation with impaired endothelial function ameliorated by BH4. | |
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MedLine Citation:
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PMID: 17848522 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 microM 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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Authors:
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Cristian Dumitrescu; Roberto Biondi; Yong Xia; Arturo J Cardounel; Lawrence J Druhan; Giuseppe Ambrosio; Jay L Zweier |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural Date: 2007-09-11 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 104 ISSN: 0027-8424 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2007 Sep |
Date Detail:
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Created Date: 2007-09-19 Completed Date: 2007-11-27 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 15081-6 Citation Subset: IM |
Affiliation:
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Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH 43210, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biopterin / analogs & derivatives*, metabolism Endothelium, Vascular / enzymology, metabolism, physiopathology* Myocardial Reperfusion Injury / enzymology, metabolism, physiopathology* Nitric Oxide / biosynthesis, metabolism Nitric Oxide Synthase / metabolism Oxidation-Reduction Rats Rats, Sprague-Dawley Superoxides / metabolism Time Factors Vasodilation |
| Grant Support | |
ID/Acronym/Agency:
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HL38324/HL/NHLBI NIH HHS; HL63744/HL/NHLBI NIH HHS; HL65608/HL/NHLBI NIH HHS; HL77575/HL/NHLBI NIH HHS; HL86965/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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10102-43-9/Nitric Oxide; 11062-77-4/Superoxides; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; EC 1.14.13.39/Nitric Oxide Synthase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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