Published online before print February 7, 2002, doi: 10.1161/01.RES.0000012569.55432.02
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 19, 2001
Revised on January 25, 2002
Accepted on January 29, 2002
Effects of Angiotensin II Infusion on the Expression and Function of NAD(P)H Oxidase and Components of Nitric Oxide/cGMP Signaling
Hanke Mollnau ;
From the Division of Cardiology (H.M., M.W., E.S., M.O., M.B., M.A., A.L.K., T. Meinertz., T. Münzel) and Cardiovascular Surgery (N.T.), University Hospital Eppendorf, Hamburg, Germany; the Department of Clinical Biochemistry and Pathobiochemistry (U.W.), University of Würzburg, Germany; the Department of Pharmacology (H.L., U.W.), Johannes Gutenberg University, Mainz, Germany; and the Department of Cardiology (K.S., B.L., K.G.), Emory University, Atlanta, Ga.
* To whom correspondence should be addressed. E-mail: muenzel{at}uke.uni-hamburg.de.
Angiotensin II infusion causes endothelial dysfunction by increasing NAD(P)H oxidase--mediated vascular superoxide production. However, it remains to be elucidated how in vivo angiotensin II treatment may alter the expression of the gp91phox isoforms and the endothelial nitric oxide synthase (NOS III) and subsequent signaling events and whether, in addition to the NAD(P)H oxidase, NOS III contributes to vascular superoxide formation. We therefore studied the influence of in vivo angiotensin II treatment (7 days) in rats on endothelial function and on the expression of the NAD(P)H oxidase subunits p22phox, nox1, nox4, and gp91phox and NOS III. Further analysis included the expression of NO-downstream targets, the soluble guanylyl cyclase (sGC), the cGMP-dependent protein kinase I (cGK-I), and the expression and phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser239 (P-VASP). Angiotensin II caused endothelial dysfunction and increased vascular superoxide. Likewise, we found an increase in vascular protein kinase C (PKC) activity, in the expression of nox1 (6- to 7-fold), gp91phox (3-fold), p22phox (3-fold), NOS III mRNA, and protein. NOS-inhibition with NG-nitro-L-arginine decreased superoxide in vessels from angiotensin II--treated animals, compatible with NOS-uncoupling. Vascular NO assessed with electron paramagnetic resonance was markedly reduced. Likewise, a decrease in sGC-expression and P-VASP levels was found. In vivo PKC-inhibition with chelerythrine reduced angiotensin II--induced superoxide production and markedly inhibited upregulation of NAD(P)H oxidase subunits. We therefore conclude that angiotensin II--induced increases in the activity and the expression of NAD(P)H oxidase are at least in part PKC-dependent. NADPH oxidase--induced superoxide production may trigger NOS III uncoupling, leading to impaired NO/cGMP signaling and to endothelial dysfunction in this animal model. The full text of this article is available at http://www.circresaha.org.
Key words: angiotensin II • hypertension • nitric oxide synthase uncoupling • nox expression • cGMP-dependent protein kinase • vasodilator-stimulated phosphoprotein
This article has been cited by other articles:
 |
|
 |
|
  K. Steinkamp-Fenske, L. Bollinger, H. Xu, Y. Yao, S. Horke, U. Forstermann, and H. Li Reciprocal Regulation of Endothelial Nitric-Oxide Synthase and NADPH Oxidase by Betulinic Acid in Human Endothelial Cells J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 836 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Zemse, R. H. P. Hilgers, and R. C. Webb Interleukin-10 counteracts impaired endothelium-dependent relaxation induced by ANG II in murine aortic rings Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3103 - H3108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Widder, T. J. Guzik, C. F.H. Mueller, R. E. Clempus, H. H.H.W. Schmidt, S. I. Dikalov, K. K. Griendling, D. P. Jones, and D. G. Harrison Role of the Multidrug Resistance Protein-1 in Hypertension and Vascular Dysfunction Caused by Angiotensin II Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 762 - 768. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Li, K. Witte, M. August, I. Brausch, U. Godtel-Armbrust, A. Habermeier, E. I. Closs, M. Oelze, T. Munzel, and U. Forstermann Reversal of Endothelial Nitric Oxide Synthase Uncoupling and Up-Regulation of Endothelial Nitric Oxide Synthase Expression Lowers Blood Pressure in Hypertensive Rats J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2536 - 2544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Polikandriotis, H. L. Rupnow, S. C. Elms, R. E. Clempus, D. J. Campbell, R. L. Sutliff, L. A. S. Brown, D. M. Guidot, and C. M. Hart Chronic Ethanol Ingestion Increases Superoxide Production and NADPH Oxidase Expression in the Lung Am. J. Respir. Cell Mol. Biol., March 1, 2006; 34(3): 314 - 319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Fitch, J. C. Rutledge, Y.-X. Wang, A. F. Powers, J.-L. Tseng, T. Clary, and G. M. Rubanyi Synergistic effect of angiotensin II and nitric oxide synthase inhibitor in increasing aortic stiffness in mice Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1190 - H1198. [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]
|
|
|
|
|
|
Z. Yuan, M. Nimata, T.-a. Okabe, K. Shioji, K. Hasegawa, T. Kita, and C. Kishimoto Olmesartan, a novel AT1 antagonist, suppresses cytotoxic myocardial injury in autoimmune heart failure Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1147 - H1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gavrila, W. G. Li, M. L. McCormick, M. Thomas, A. Daugherty, L. A. Cassis, F. J. Miller Jr, L. W. Oberley, K. C. Dellsperger, and N. L. Weintraub Vitamin E Inhibits Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1671 - 1677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Chalupsky and H. Cai Endothelial dihydrofolate reductase: Critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase PNAS, June 21, 2005; 102(25): 9056 - 9061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gao, W. Wang, Y.-L. Li, H. D. Schultz, D. Liu, K. G. Cornish, and I. H. Zucker Sympathoexcitation by central ANG II: Roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2271 - H2279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Laude, H. Cai, B. Fink, N. Hoch, D. S. Weber, L. McCann, G. Kojda, T. Fukai, H. H. H. W. Schmidt, S. Dikalov, et al. Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H7 - H12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Weber, P. Rocic, A. M. Mellis, K. Laude, A. N. Lyle, D. G. Harrison, and K. K. Griendling Angiotensin II-induced hypertrophy is potentiated in mice overexpressing p22phox in vascular smooth muscle Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H37 - H42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Lu, B. G. Helwig, R. J. Fels, S. Parimi, and M. J. Kenney Central Tempol alters basal sympathetic nerve discharge and attenuates sympathetic excitation to central ANG II Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2626 - H2633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Hare Nitroso-Redox Balance in the Cardiovascular System N. Engl. J. Med., November 11, 2004; 351(20): 2112 - 2114. [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Li and A. M Shah Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1014 - R1030. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Ungvari, A. Csiszar, P. M. Kaminski, M. S. Wolin, and A. Koller Chronic High Pressure-Induced Arterial Oxidative Stress: Involvement of Protein Kinase C-Dependent NAD(P)H Oxidase and Local Renin-Angiotensin System Am. J. Pathol., July 1, 2004; 165(1): 219 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Sowers Insulin resistance and hypertension Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1597 - H1602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Schulz, M. Kelm, and G. Heusch Nitric oxide in myocardial ischemia/reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 402 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Paravicini, S. Chrissobolis, G. R. Drummond, and C. G. Sobey Increased NADPH-Oxidase Activity and Nox4 Expression During Chronic Hypertension Is Associated With Enhanced Cerebral Vasodilatation to NADPH In Vivo Stroke, February 1, 2004; 35(2): 584 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Li and A. M. Shah ROS Generation by Nonphagocytic NADPH Oxidase: Potential Relevance in Diabetic Nephropathy J. Am. Soc. Nephrol., August 1, 2003; 14(90003): S221 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. O. Bonetti, D. R. Holmes Jr, A. Lerman, and G. W. Barsness Enhanced external counterpulsation for ischemic heart disease: What's behind the curtain? J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1918 - 1925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Lombard, F. A. Sylvester, S. A. Phillips, and J. C. Frisbee High-salt diet impairs vascular relaxation mechanisms in rat middle cerebral arteries Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1124 - H1133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. X. Zhang, A.-P. Zou, and P.-L. Li Ceramide-induced activation of NADPH oxidase and endothelial dysfunction in small coronary arteries Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H605 - H612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. E. Rey and P. J. Pagano The Reactive Adventitia: Fibroblast Oxidase in Vascular Function Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1962 - 1971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. E. Rey, X.-C. Li, O. A. Carretero, J. L. Garvin, and P. J. Pagano Perivascular Superoxide Anion Contributes to Impairment of Endothelium-Dependent Relaxation: Role of gp91phox Circulation, November 5, 2002; 106(19): 2497 - 2502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Sowers Hypertension, Angiotensin II, and Oxidative Stress N. Engl. J. Med., June 20, 2002; 346(25): 1999 - 2001. [Full Text] [PDF]
|
|