Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain

Matthew C Zimmerman; Ryan P Dunlay; Eric Lazartigues; Yulong Zhang; Ram V Sharma; John F Engelhardt; Robin L Davisson

doi:10.1161/01.RES.0000139957.22530.b9

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Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain

Journal article

Open access

Peer reviewed

Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain

Matthew C Zimmerman, Ryan P Dunlay, Eric Lazartigues, Yulong Zhang, Ram V Sharma, John F Engelhardt and Robin L Davisson

Circulation research, Vol.95(5), pp.532-539

09/03/2004

DOI: 10.1161/01.RES.0000139957.22530.b9

PMID: 15271858

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Abstract

We have shown that intracellular superoxide (O(2)(*-)) 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 O(2)(*-) 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 O(2)(*-) 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 O(2)(*-) 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 O(2)(*-) scavenging. These results, for the first time, identify a Rac1-dependent NADPH oxidase as the source of central Ang II-induced O(2)(*-) production, and implicate this oxidase in cardiovascular diseases associated with dysregulation of brain Ang II signaling, including hypertension.

Signal Transduction

Cell Line

Angiotensin II - pharmacology

Brain - cytology

Mice, Inbred C57BL

Brain - enzymology

Brain - physiology

Heart Rate - drug effects

Animals

rac1 GTP-Binding Protein - physiology

Neurons - enzymology

Superoxides - metabolism

Adenoviridae - genetics

Blood Pressure - drug effects

Drinking - drug effects

Mice

Neurons - metabolism

Genetic Vectors

Neurons - drug effects

Transgenes

NADPH Oxidases - physiology

rac1 GTP-Binding Protein - genetics

Details

Title: Subtitle: Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain
Creators: Matthew C Zimmerman - Department of Anatomy and Cell Biology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City 52242, USA
Ryan P Dunlay
Eric Lazartigues
Yulong Zhang
Ram V Sharma
John F Engelhardt
Robin L Davisson
Resource Type: Journal article
Publication Details: Circulation research, Vol.95(5), pp.532-539
DOI: 10.1161/01.RES.0000139957.22530.b9
PMID: 15271858
NLM abbreviation: Circ Res
ISSN: 0009-7330
eISSN: 1524-4571
Publisher: United States
Grant note: HL-63887 / NHLBI NIH HHS HL-14388 / NHLBI NIH HHS
Language: English
Date published: 09/03/2004
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984025466702771

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