Published online before print July 22, 2004, doi: 10.1161/01.RES.0000139957.22530.b9
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Submitted on April 12, 2004
Revised on July 8, 2004
Accepted on July 12, 2004
Requirement for Rac1-Dependent NADPH Oxidase in the Cardiovascular and Dipsogenic Actions of Angiotensin II in the Brain
Matthew C. Zimmerman ;
From the Department of Anatomy and Cell Biology (M.C.Z., R.P.D., E.L., Y.Z., R.V.S., J.F.E., R.L.D.), the Free Radical and Radiation Biology Program, the Department of Radiation Oncology (M.C.Z., R.L.D.), the Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases (Y.Z., J.F.E., R.L.D.), The Cardiovascular Center (R.V.S., R.L.D.), The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City.
* To whom correspondence should be addressed. E-mail: robin-davisson{at}uiowa.edu.
We have shown that intracellular superoxide (O2·-) production in CNS neurons plays a key role in the pressor, bradycardic, and dipsogenic actions of Ang II in the brain. In this study, we tested the hypothesis that a Rac1-dependent NADPH oxidase is a key source of O2·- in Ang II-sensitive neurons and is involved in these central Ang II-dependent effects. We performed both in vitro and in vivo studies using adenoviral (Ad)-mediated expression of dominant-negative Rac1 (AdN17Rac1) to inhibit Ang II-stimulated Rac1 activation, an obligatory step in NADPH oxidase activation. Ang II induced a time-dependent increase in Rac1 activation and O2·- production in Neuro-2A cells, and this was abolished by pretreatment with AdN17Rac1 or the NADPH oxidase inhibitors apocynin or diphenylene iodonium. AdN17Rac1 also inhibited Ang II-induced increases in NADPH oxidase activity in primary neurons cultured from central cardiovascular control regions. In contrast, overexpression of wild-type Rac1 (AdwtRac1) caused more robust NADPH oxidase-dependent O2·- production to Ang II. To extend the in vitro studies, the pressor, bradycardic, and drinking responses to intracerebroventricularly (ICV) injected Ang II were measured in mice that had undergone gene transfer of AdN17Rac1 or AdwtRac1 to the brain. AdN17Rac1 abolished the increase in blood pressure, decrease in heart rate, and drinking response induced by ICV injection of Ang II, whereas AdwtRac1 enhanced these physiological effects. The exaggerated physiological responses in AdwtRac1-treated mice were abolished by O2·- scavenging. These results, for the first time, identify a Rac1-dependent NADPH oxidase as the source of central Ang II-induced O2·- production, and implicate this oxidase in cardiovascular diseases associated with dysregulation of brain Ang II signaling, including hypertension.
Key words: reactive oxygen species • dominant-negative Rac1 • blood pressure • dipsogenic response • neurons
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