Document Detail


Myocardial ischemia results in tetrahydrobiopterin (BH4) oxidation with impaired endothelial function ameliorated by BH4.
MedLine Citation:
PMID:  17848522     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Cristian Dumitrescu; Roberto Biondi; Yong Xia; Arturo J Cardounel; Lawrence J Druhan; Giuseppe Ambrosio; Jay L Zweier
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2007-09-11
Journal Detail:
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:
Created Date:  2007-09-19     Completed Date:  2007-11-27     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15081-6     Citation Subset:  IM    
Affiliation:
Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH 43210, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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:
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

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