© 1997 American Heart Association, Inc.
Articles |
Angiotensin II Induces Apoptosis of Human Endothelial Cells
Protective Effect of Nitric Oxide
From Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt (Germany).
Correspondence to Stefanie Dimmeler, PhD, Department of Internal Medicine IV, Division of Cardiology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Dimmeler{at}em.uni-frankfurt.de
Abstract Angiotensin II (Ang II) importantly contributes to the pathobiology of atherosclerosis. Since endothelial injury is a key event early in the pathogenesis of atherosclerosis, we tested the hypothesis that Ang II may injure endothelial cells by activation of cellular suicide pathways leading to apoptosis. Human umbilical venous endothelial cells (HUVECs) were incubated with increasing doses of Ang II for 18 hours. Apoptosis of HUVECs was measured by ELISA specific for histone-associated DNA fragments and confirmed by DNA laddering and nuclear staining. Ang II dose-dependently induced apoptosis of HUVECs. Simultaneous blockade of both the AT1 and AT2 receptor prevented Ang II–induced apoptosis, whereas each individual receptor blocker alone was not effective. Selective agonistic stimulation of the AT2 receptor also dose-dependently induced apoptosis. Ang II–mediated as well as selective AT2 receptor stimulation–mediated apoptosis was associated with the activation of caspase-3, a central downstream effector of the caspase cascade executing the cell death program. Specific inhibition of caspase-3 activity abrogated Ang II–induced apoptosis. In addition, the NO donors sodium nitroprusside and S-nitrosopenicillamine completely inhibited Ang II–induced apoptosis and eliminated caspase-3 activity. Thus, Ang II induces apoptosis of HUVECs via activation of the caspase cascade, the central downstream effector arm executing the cell death program. NO completely abrogated Ang II–induced apoptosis by interfering with the activation of the caspase cascade.
Key Words: CPP32 • protease • CGP42112 • PD123177 • EXP3174
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D. Y. Li, Y. C. Zhang, M. I. Philips, T. Sawamura, and J. L. Mehta Upregulation of Endothelial Receptor for Oxidized Low-Density Lipoprotein (LOX-1) in Cultured Human Coronary Artery Endothelial Cells by Angiotensin II Type 1 Receptor Activation Circ. Res., May 14, 1999; 84(9): 1043 - 1049. [Abstract] [Full Text] [PDF]
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R. Wang, A. Zagariya, O. Ibarra-Sunga, C. Gidea, E. Ang, S. Deshmukh, G. Chaudhary, J. Baraboutis, G. Filippatos, and B. D. Uhal Angiotensin II induces apoptosis in human and rat alveolar epithelial cells Am J Physiol Lung Cell Mol Physiol, May 1, 1999; 276(5): L885 - L889. [Abstract] [Full Text] [PDF]
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M. Horiuchi, W. Hayashida, M. Akishita, K. Tamura, L. Daviet, J. Y. A. Lehtonen, and V. J. Dzau Stimulation of Different Subtypes of Angiotensin II Receptors, AT1 and AT2 Receptors, Regulates STAT Activation by Negative Crosstalk Circ. Res., April 30, 1999; 84(8): 876 - 882. [Abstract] [Full Text] [PDF]
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M. Horiuchi, M. Akishita, and V. J. Dzau Recent Progress in Angiotensin II Type 2 Receptor Research in the Cardiovascular System Hypertension, February 1, 1999; 33(2): 613 - 621. [Abstract] [Full Text] [PDF]
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D. J. Ing, J. Zang, V. J. Dzau, K. A. Webster, and N. H. Bishopric Modulation of Cytokine-Induced Cardiac Myocyte Apoptosis by Nitric Oxide, Bak, and Bcl-x Circ. Res., January 22, 1999; 84(1): 21 - 33. [Abstract] [Full Text] [PDF]
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U. V. Shenoy, E. M. Richards, X.-C. Huang, and C. Sumners Angiotensin II Type 2 Receptor-Mediated Apoptosis of Cultured Neurons from Newborn Rat Brain Endocrinology, January 1, 1999; 140(1): 500 - 509. [Abstract] [Full Text]
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P. J. M. Best, D. Hasdai, G. Sangiorgi, R. S. Schwartz, D. R. Holmes Jr, R. D. Simari, and A. Lerman Apoptosis : Basic Concepts and Implications in Coronary Artery Disease Arterioscler Thromb Vasc Biol, January 1, 1999; 19(1): 14 - 22. [Abstract] [Full Text] [PDF]
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M. Horiuchi, H. Yamada, M. Akishita, M. Ito, K. Tamura, and V. J. Dzau Interferon Regulatory Factors Regulate Interleukin-1ß–Converting Enzyme Expression and Apoptosis in Vascular Smooth Muscle Cells Hypertension, January 1, 1999; 33(1): 162 - 166. [Abstract] [Full Text] [PDF]
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J.-D. Chiche, S. M. Schlutsmeyer, D. B. Bloch, S. M. de la Monte, J. D. Roberts Jr., G. Filippov, S. P. Janssens, A. Rosenzweig, and K. D. Bloch Adenovirus-mediated Gene Transfer of cGMP-dependent Protein Kinase Increases the Sensitivity of Cultured Vascular Smooth Muscle Cells to the Antiproliferative and Pro-apoptotic Effects of Nitric Oxide/cGMP J. Biol. Chem., December 18, 1998; 273(51): 34263 - 34271. [Abstract] [Full Text] [PDF]
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A. M. Diehl Roles of CCAAT/Enhancer-binding Proteins in Regulation of Liver Regenerative Growth J. Biol. Chem., November 20, 1998; 273(47): 30843 - 30846. [Abstract] [Full Text] [PDF]
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D. H. Walter, J. Haendeler, J. Galle, A. M. Zeiher, and S. Dimmeler Cyclosporin A Inhibits Apoptosis of Human Endothelial Cells by Preventing Release of Cytochrome C From Mitochondria Circulation, September 22, 1998; 98(12): 1153 - 1157. [Abstract] [Full Text] [PDF]
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S. Kotamraju, N. Hogg, J. Joseph, L. K. Keefer, and B. Kalyanaraman Inhibition of Oxidized Low-density Lipoprotein-induced Apoptosis in Endothelial Cells by Nitric Oxide. PEROXYL RADICAL SCAVENGING AS AN ANTIAPOPTOTIC MECHANISM J. Biol. Chem., May 11, 2001; 276(20): 17316 - 17323. [Abstract] [Full Text] [PDF]
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U. Schmitz, K. Thommes, I. Beier, W. Wagner, A. Sachinidis, R. Dusing, and H. Vetter Angiotensin II-induced Stimulation of p21-activated Kinase and c-Jun NH2-terminal Kinase Is Mediated by Rac1 and Nck J. Biol. Chem., June 15, 2001; 276(25): 22003 - 22010. [Abstract] [Full Text] [PDF]
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J.-R. Nofer, B. Levkau, I. Wolinska, R. Junker, M. Fobker, A. von Eckardstein, U. Seedorf, and G. Assmann Suppression of Endothelial Cell Apoptosis by High Density Lipoproteins (HDL) and HDL-associated Lysosphingolipids J. Biol. Chem., September 7, 2001; 276(37): 34480 - 34485. [Abstract] [Full Text] [PDF]
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J. Hoffmann, J. Haendeler, A. Aicher, L. Rossig, M. Vasa, A. M. Zeiher, and S. Dimmeler Aging Enhances the Sensitivity of Endothelial Cells Toward Apoptotic Stimuli: Important Role of Nitric Oxide Circ. Res., October 12, 2001; 89(8): 709 - 715. [Abstract] [Full Text] [PDF]
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F. J. Miller Jr, W. J. Sharp, X. Fang, L. W. Oberley, T. D. Oberley, and N. L. Weintraub Oxidative Stress in Human Abdominal Aortic Aneurysms: A Potential Mediator of Aneurysmal Remodeling Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 560 - 565. [Abstract] [Full Text] [PDF]
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