Circulation. 2003;108:1567-1574
Published online before print September 8, 2003, doi: 10.1161/01.CIR.0000091084.46500.BB
Published online before print September 8, 2003, doi: 10.1161/01.CIR.0000091084.46500.BB
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(Circulation. 2003;108:1567.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Oxygen Free Radical Release in Human Failing Myocardium Is Associated With Increased Activity of Rac1-GTPase and Represents a Target for Statin Treatment
From Klinik und Poliklinik für Innere Medizin III (C.M., T.K., H.K., G.N., M.B., U.L.), Universität des Saarlandes, Homburg/Saar, Germany; Institute of Molecular Cardiobiology (C.M.), Johns Hopkins University, Baltimore, Md; and Klinik für Herz- und Thoraxchirurgie (H.-J.S.), Universität des Saarlandes, Homburg/Saar, Germany.
Correspondence to Ulrich Laufs, MD, Klinik und Poliklinik für Innere Medizin III, Universität des Saarlandes, 66424 Homburg/Saar, Germany. E-mail ulrich{at}laufs.com
Received February 18, 2003; de novo received May 29, 2003; revision received July 18, 2003; accepted July 21, 2003.
Background— Reactive oxygen species (ROS) contribute to the development of heart failure. A potential source of myocardial ROS is the NADPH oxidase, which is regulated by the small GTP-binding protein rac1. Isoprenylation of rac1 can be inhibited by statin therapy. Thus, we examined ROS and rac1 in human failing myocardium and tested their regulation by statins in vivo.
Methods and Results— In human left ventricular myocardium from patients with ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM), NADPH oxidase activity was increased 1.5-fold compared with nonfailing controls (P<0.05, n=8). In failing myocardium, increased oxidative stress determined by measurements of lipid peroxidation and aconitase activity was associated with increased translocation of rac1 from the cytosol to the membrane. Pull-down assays revealed a 3-fold increase of rac1-GTPase activity in ICM and DCM. In parallel, membrane expression of the NADPH oxidase subunit p47phox, but not p67phox, was upregulated in failing compared with nonfailing myocardium. In right atrial myocardium from patients undergoing cardiac surgery who were prospectively treated with atorvastatin or pravastatin (40 mg/d, 4 weeks), rac1-GTPase activity was decreased to 67.9±12% and 65.6±13.8% compared with patients without statin (P<0.05, n=8). Both atorvastatin and pravastatin significantly reduced angiotensin II–stimulated but not basal NADPH oxidase activity.
Conclusions— Failing myocardium of patients with DCM and ICM is characterized by upregulation of NADPH oxidase–mediated ROS release associated with increased rac1 activity. Oral statin treatment inhibits myocardial rac1-GTPase activity. These data suggest that extrahepatic effects of statins can be observed in humans and may be beneficial for patients with chronic heart failure.
Key Words: heart failure • myocardium • inhibitors • free radicals • statins
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 H. Mollnau, M. Oelze, M. August, M. Wendt, A. Daiber, E. Schulz, S. Baldus, A. L. Kleschyov, A. Materne, P. Wenzel, et al. Mechanisms of Increased Vascular Superoxide Production in an Experimental Model of Idiopathic Dilated Cardiomyopathy Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2554 - 2559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Wolin and S. A. Gupte Novel Roles for Nox Oxidases in Cardiac Arrhythmia and Oxidized Glutathione Export in Endothelial Function Circ. Res., September 30, 2005; 97(7): 612 - 614. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
E. O. Weinberg, M. Scherrer-Crosbie, M. H. Picard, B. A. Nasseri, C. MacGillivray, J. Gannon, Q. Lian, K. D. Bloch, and R. T. Lee Rosuvastatin reduces experimental left ventricular infarct size after ischemia-reperfusion injury but not total coronary occlusion Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1802 - H1809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Madamanchi, A. Vendrov, and M. S. Runge Oxidative Stress and Vascular Disease Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 29 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Srivastava, M. Spite, J. O. Trent, M. B. West, Y. Ahmed, and A. Bhatnagar Aldose Reductase-catalyzed Reduction of Aldehyde Phospholipids J. Biol. Chem., December 17, 2004; 279(51): 53395 - 53406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Nickenig Should Angiotensin II Receptor Blockers and Statins Be Combined? Circulation, August 24, 2004; 110(8): 1013 - 1020. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
M. Maytin, D. A. Siwik, M. Ito, L. Xiao, D. B. Sawyer, R. Liao, and W. S. Colucci Pressure Overload-Induced Myocardial Hypertrophy in Mice Does Not Require gp91phox Circulation, March 9, 2004; 109(9): 1168 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
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