Myocardial ischemia results in tetrahydrobiopterin (BH4) oxidation with impaired endothelial function ameliorated by BHIN4

Cristian Dumitrescu, Roberto Biondi, Yong Xia, Arturo J. Cardounel, Lawrence J. Druhan, Giuseppe Ambrosio, Jay L. Zweier

Research output: Contribution to journalArticle

Abstract

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 (BH4); however, the role of BH4 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 BH4 concentrations. Ischemia time-dependently decreased cardiac BH4 content with 85, 95, or 97% irreversible degradation after 30, 45, or 60 min of ischemia, respectively. Paralleling the decreases in BH4, reductions of eNOS activity were seen of 58, 86, or 92%, and NOS-derived superoxide production was greatly increased. Addition of 10 μM BH4 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 BH4 infusion. Thus, BH4 depletion contributes to postischemic eNOS dysfunction, and BH4 treatment is effective in partial restoration of endothelium-dependent coronary flow. Supplementation of BH4 may therefore be an important therapeutic approach to reverse endothelial dysfunction in postischemic tissues.

Original languageEnglish (US)
Pages (from-to)15081-15086
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number38
DOIs
StatePublished - Sep 18 2007
Externally publishedYes

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Keywords

  • Ischemia reperfusion injury
  • Nitric oxide
  • Nitric oxide synthase uncoupling
  • Superoxide
  • Vascular function

ASJC Scopus subject areas

  • Genetics
  • General

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