Bradykinin-induced dilation of human coronary arterioles requires nadph oxidase-derived reactive oxygen species

Brandon T. Larsen, Aaron H. Bubolz, Suelhem A. Mendoza, Kirkwood A. Pritchard, David D. Gutterman

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

OBJECTIVE-: Hydrogen peroxide (H 2O 2) is an endothelium-derived hyperpolarizing factor in human coronary arterioles (HCAs). H 2O 2 mediates bradykinin (BK)-induced vasodilation and reduces bioavailability of epoxyeicosatrienoic acids (EETs); however, the cellular and enzymatic source of H 2O 2 is unknown. METHODS AND RESULTS-: NADPH oxidase expression was determined by immunohistochemistry. Superoxide and H 2O 2 production was assayed in HCAs and human coronary artery endothelial cells (HCAECs) using dihydroethidium and dichlorodihydrofluorescein histofluorescence, respectively. Superoxide was quantified by HPLC separation of dihydroethidium products. Diameter changes of HCAs were measured by videomicroscopy. NADPH oxidase subunits Nox1, Nox2, Nox4, p22, p47, and p67 were each expressed in HCA endothelium. In HCAs or HCAECs incubated with dihydroethidium and dichlorodihydrofluorescein, BK induced superoxide and H 2O 2 formation, which was inhibited by gp91ds-tat or apocynin but not by gp91scram-tat or rotenone. HPLC analysis confirmed that BK specifically induced superoxide production. Gp91ds-tat reduced vasodilation to BK but not to papaverine. 14,15-EEZE (an EET antagonist) further reduced the residual dilation to BK in the presence of gp91ds-tat, but had no effect in the presence of gp91scram-tat, suggesting that NADPH oxidase-derived ROS modulate EET bioavailability. CONCLUSION-: We conclude that endothelial NADPH oxidase is a functionally relevant source of H2O2 that mediates agonist-induced dilation in the human heart.

Original languageEnglish (US)
Pages (from-to)739-745
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume29
Issue number5
DOIs
StatePublished - May 2009

Keywords

  • Coronary circulation
  • Endothelium
  • Hypertension-basic studies
  • Neurohumoral control of circulation
  • Oxidant stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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