Published online before print July 22, 2004, doi: 10.1161/01.RES.0000139957.22530.b9
© 2004 American Heart Association, Inc.
Integrative Physiology |
Requirement for Rac1-Dependent NADPH Oxidase in the Cardiovascular and Dipsogenic Actions of Angiotensin II in the Brain
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.
Correspondence to Robin L. Davisson, PhD, Department of Anatomy and Cell Biology, 1-418 Bowen Science Bldg, The University of Iowa College of Medicine, Iowa City, IA 52242. 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
This article has been cited by other articles:
 |
|
 |
|
  T. E. Lindley, D. W. Infanger, M. Rishniw, Y. Zhou, M. F. Doobay, R. V. Sharma, and R. L. Davisson Scavenging superoxide selectively in mouse forebrain is associated with improved cardiac function and survival following myocardial infarction Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2009; 296(1): R1 - R8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Xue, Y. Zhao, A. K. Johnson, and M. Hay Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1025 - H1032. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Belmadani, M. Zerfaoui, H. A. Boulares, D. I. Palen, and K. Matrougui Microvessel vascular smooth muscle cells contribute to collagen type I deposition through ERK1/2 MAP kinase, {alpha}v{beta}3-integrin, and TGF-{beta}1 in response to ANG II and high glucose Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H69 - H76. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Hoffmann, C. J. Weydert, E. Lazartigues, W. J. Kutschke, M. F. Kienzle, J. E. Leach, J. A. Sharma, R. V. Sharma, and R. L. Davisson Chronic Tempol Prevents Hypertension, Proteinuria, and Poor Feto-Placental Outcomes in BPH/5 Mouse Model of Preeclampsia Hypertension, April 1, 2008; 51(4): 1058 - 1065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Guzik, N. E. Hoch, K. A. Brown, L. A. McCann, A. Rahman, S. Dikalov, J. Goronzy, C. Weyand, and D. G. Harrison Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction J. Exp. Med., October 1, 2007; 204(10): 2449 - 2460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Cao, X. Dai, L. M. Parker, and D. L. Kreulen Differential Regulation of NADPH Oxidase in Sympathetic and Sensory Ganglia in Deoxycorticosterone Acetate Salt Hypertension Hypertension, October 1, 2007; 50(4): 663 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nozoe, Y. Hirooka, Y. Koga, Y. Sagara, T. Kishi, J. F. Engelhardt, and K. Sunagawa Inhibition of Rac1-Derived Reactive Oxygen Species in Nucleus Tractus Solitarius Decreases Blood Pressure and Heart Rate in Stroke-Prone Spontaneously Hypertensive Rats Hypertension, July 1, 2007; 50(1): 62 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Chen and H.-L. Pan Signaling Mechanisms of Angiotensin II-Induced Attenuation of GABAergic Input to Hypothalamic Presympathetic Neurons J Neurophysiol, May 1, 2007; 97(5): 3279 - 3287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-X. Pan, L. Gao, W.-Z. Wang, H. Zheng, D. Liu, K. P. Patel, I. H. Zucker, and W. Wang Exercise Training Prevents Arterial Baroreflex Dysfunction in Rats Treated With Central Angiotensin II Hypertension, March 1, 2007; 49(3): 519 - 527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Sinnayah, E. Lazartigues, K. Sakai, R. V. Sharma, C. D. Sigmund, and R. L. Davisson Genetic Ablation of Angiotensinogen in the Subfornical Organ of the Brain Prevents the Central Angiotensinergic Pressor Response Circ. Res., November 10, 2006; 99(10): 1125 - 1131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Hingtgen, X. Tian, J. Yang, S. M. Dunlay, A. S. Peek, Y. Wu, R. V. Sharma, J. F. Engelhardt, and R. L. Davisson Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy Physiol Genomics, September 14, 2006; 26(3): 180 - 191. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Paravicini and R. M. Touyz Redox signaling in hypertension Cardiovasc Res, July 15, 2006; 71(2): 247 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zhou, C. Ziegler, L. A. Birder, A. F.R. Stewart, and E. S. Levitan Angiotensin II and Stretch Activate NADPH Oxidase to Destabilize Cardiac Kv4.3 Channel mRNA Circ. Res., April 28, 2006; 98(8): 1040 - 1047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dodic, A. T. McAlinden, A. J. Jefferies, E. M. Wintour, M. L. Cock, C. N. May, R. G. Evans, and K. M. Moritz Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep J. Physiol., March 15, 2006; 571(3): 651 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sherrod, D. R. Davis, X. Zhou, M. D. Cassell, and C. D. Sigmund Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1763 - R1769. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. H. Zucker and L. Gao The Regulation of Sympathetic Nerve Activity by Angiotensin II Involves Reactive Oxygen Species and MAPK Circ. Res., October 14, 2005; 97(8): 737 - 739. [Full Text] [PDF]
|
|
|
|
|
|
S. H.H. Chan, K.-S. Hsu, C.-C. Huang, L.-L. Wang, C.-C. Ou, and J. Y.H. Chan NADPH Oxidase-Derived Superoxide Anion Mediates Angiotensin II-Induced Pressor Effect via Activation of p38 Mitogen-Activated Protein Kinase in the Rostral Ventrolateral Medulla Circ. Res., October 14, 2005; 97(8): 772 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Gao, W. Wang, Y.-L. Li, H. D. Schultz, D. Liu, K. G. Cornish, and I. H. Zucker Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure: Roles of Angiotensin II Type 1 Receptors and NAD(P)H Oxidase Circulation, September 20, 2005; 112(12): 1763 - 1770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Sun, K. W. Sellers, C. Sumners, and M. K. Raizada NAD(P)H Oxidase Inhibition Attenuates Neuronal Chronotropic Actions of Angiotensin II Circ. Res., April 1, 2005; 96(6): 659 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Zimmerman, R. V. Sharma, and R. L. Davisson Superoxide Mediates Angiotensin II-Induced Influx of Extracellular Calcium in Neural Cells Hypertension, April 1, 2005; 45(4): 717 - 723. [Abstract] [Full Text] [PDF]
|
|