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Bradykinin-induced dilation of human coronary arterioles requires NADPH oxidase-derived reactive oxygen species. Arterioscler Thromb Vasc Biol 2009 May;29(5):739-45



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Scopus ID

2-s2.0-65549163547   52 Citations


OBJECTIVE: Hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor in human coronary arterioles (HCAs). H2O2 mediates bradykinin (BK)-induced vasodilation and reduces bioavailability of epoxyeicosatrienoic acids (EETs); however, the cellular and enzymatic source of H2O2 is unknown.

METHODS AND RESULTS: NADPH oxidase expression was determined by immunohistochemistry. Superoxide and H2O2 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 H2O2 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.

Author List

Larsen BT, Bubolz AH, Mendoza SA, Pritchard KA Jr, Gutterman DD


David D. Gutterman MD Sr Associate Director, Professor in the Medicine department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged, 80 and over
Coronary Vessels
Hydrogen Peroxide
Middle Aged
NADPH Oxidases
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a