Published online before print July 21, 2003, doi: 10.1161/01.CIR.0000079165.84309.4D
(Circulation. 2003;108:1253.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
High Pressure Induces Superoxide Production in Isolated Arteries Via Protein Kinase C–Dependent Activation of NAD(P)H Oxidase
From the Department of Physiology, New York Medical College, Valhalla, NY (Z.U., A.C., A.N., P.M.K., M.S.W., A.K.), and the Department of Pathophysiology, Semmelweis University, Budapest, Hungary (Z.U., A.C., A.K.).
Correspondence to Akos Koller MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail koller{at}nymc.edu
Received February 3, 2003; revision received April 29, 2003; accepted May 2, 2003.
Background— Oxidative stress seems to be present in all forms of hypertension. Thus, we tested the hypothesis that high intraluminal pressure (Pi) itself, by activating vascular oxidases, elicits increased superoxide (O2·-) production interfering with flow-induced dilation.
Methods and Results— Isolated, cannulated rat femoral arterial branches were exposed in vitro (for 30 minutes) to normal Pi (80 mm Hg) or high Pi (160 mm Hg). High Pi significantly increased vascular O2·- production (as measured by lucigenin chemiluminescence and ethidium bromide fluorescence) and impaired endothelium-dependent dilations to flow; these effects could be reversed by superoxide dismutase. Administration of the NAD(P)H oxidase inhibitor diphenyleneiodonium, apocynin, the protein kinase C (PKC) inhibitor chelerythrine or staurosporin or the removal of extracellular Ca2+ during high Pi treatment prevented the increases in O2·- production, whereas administration of losartan or captopril had no effect. High Pi resulted in significant increases in intracellular Ca2+ ([Ca2+]i) in the vascular wall (fura 2 fluorescence) and phosphorylation of PKC
(Western blotting). The PKC activator phorbol myristate acetate significantly increased vascular O2·- production, which was inhibited by superoxide dismutase, diphenyleneiodonium, chelerythrine, or removal of extracellular Ca2+. Both high Pi and phorbol myristate acetate increased the phosphorylation of the NAD(P)H oxidase subunit p47phox.
Conclusion— High Pi itself elicits arterial O2·- production, most likely by PKC-dependent activation of NAD(P)H oxidase, thus providing a potential explanation for the presence of oxidative stress and endothelial dysfunction in various forms of hypertension and the vasculoprotective effect of antihypertensive agents of different mechanisms of action.
Key Words: signal transduction • hypertension • angiotensin • endothelium • peripheral vascular disease
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