(Circulation. 1997;95:1760-1763.)
© 1997 American Heart Association, Inc.
Articles |
Oxidized Low-Density Lipoprotein Induces Apoptosis of Human Endothelial Cells by Activation of CPP32-Like Proteases
A Mechanistic Clue to the `Response to Injury' Hypothesis
From Molecular Cardiology (S.D., J.H., A.M.Z.), Department of Internal Medicine IV, University of Frankfurt, and Department of Nephrology (J.G.), University of Würzburg (Germany).
Correspondence to Andreas M. Zeiher, MD, Department of Internal Medicine IV, Division of Cardiology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Zeiher{at}em.uni-frankfurt.de
Background Oxidized LDL (oxLDL) is believed to play a key role as a triggering molecule that causes injury to the endothelium as an early event in atherogenesis. However, the mechanisms by which oxLDL injures endothelial cells are entirely unknown. We speculate that oxLDL may activate a cellular suicide pathway that leads to apoptosis.
Methods and Results Human umbilical venous endothelial cells (HUVEC) were incubated with increasing doses of native or oxLDL for 18 hours. Apoptosis of HUVEC was measured with an ELISA specific for histone-associated DNA fragments and confirmed with DNA laddering. Native LDL had no effect, but incubation with oxLDL dose-dependently induced apoptosis of HUVEC. Induction of apoptosis by oxLDL was associated with increased CPP32-like protease activity, which is the major enzyme that initiates the proteolytical cascade leading to cell death. Specific inhibition of CPP32 activity completely abrogated oxLDL-induced apoptosis. The antioxidants N-acetylcysteine and the combination of vitamins C and E prevented oxLDL-induced apoptosis, abrogated the enhancement of CPP32-like protease activity, and inhibited the proteolytic cleavage of CPP32 into its active subunit p17.
Conclusions oxLDL activates the suicide pathway leading to apoptosis of endothelial cells by enhancing CPP32-like protease activity. The oxLDL-mediated activation of CPP32 appears to involve the elaboration of reactive oxygen species. Activation of the cell death effector CPP32 by oxLDL may provide a mechanistic clue to the "response-to-injury" hypothesis of atherogenesis.
Key Words: cells • endothelium • lipoproteins • atherogenesis • apoptosis
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 D. J. Granville, J. R. Shaw, S. Leong, C. M. Carthy, P. Margaron, D. W. Hunt, and B. M. McManus Release of Cytochrome c, Bax Migration, Bid Cleavage, and Activation of Caspases 2, 3, 6, 7, 8, and 9 during Endothelial Cell Apoptosis Am. J. Pathol., October 1, 1999; 155(4): 1021 - 1025. [Abstract] [Full Text] [PDF]
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 C. J. Vaughan and N. Delanty Neuroprotective Properties of Statins in Cerebral Ischemia and Stroke Stroke, September 1, 1999; 30(9): 1969 - 1973. [Abstract] [Full Text] [PDF]
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H. Morawietz, U. Rueckschloss, B. Niemann, N. Duerrschmidt, J. Galle, K. Hakim, H.-R. Zerkowski, T. Sawamura, and J. Holtz Angiotensin II Induces LOX-1, the Human Endothelial Receptor for Oxidized Low-Density Lipoprotein Circulation, August 31, 1999; 100(9): 899 - 902. [Abstract] [Full Text] [PDF]
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A. M Dart and J. P.F Chin-Dusting Lipids and the endothelium Cardiovasc Res, August 1, 1999; 43(2): 308 - 322. [Abstract] [Full Text] [PDF]
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 S. Dimmeler, K. Breitschopf, J. Haendeler, and A. M. Zeiher Dephosphorylation Targets Bcl-2 for Ubiquitin-dependent Degradation: A Link between the Apoptosome and the Proteasome Pathway J. Exp. Med., June 7, 1999; 189(11): 1815 - 1822. [Abstract] [Full Text] [PDF]
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O. MEILHAC, I. ESCARGUEIL-BLANC, J.-C. THIERS, R. SALVAYRE, and A. NÈGRE-SALVAYRE Bcl-2 alters the balance between apoptosis and necrosis, but does not prevent cell death induced by oxidized low density lipoproteins FASEB J, March 1, 1999; 13(3): 485 - 494. [Abstract] [Full Text]
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S. Dimmeler, C. Hermann, J. Galle, and A. M. Zeiher Upregulation of Superoxide Dismutase and Nitric Oxide Synthase Mediates the Apoptosis-Suppressive Effects of Shear Stress on Endothelial Cells Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 656 - 664. [Abstract] [Full Text] [PDF]
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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. Sata and K. Walsh Endothelial Cell Apoptosis Induced by Oxidized LDL Is Associated with the Down-regulation of the Cellular Caspase Inhibitor FLIP J. Biol. Chem., December 11, 1998; 273(50): 33103 - 33106. [Abstract] [Full Text] [PDF]
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P. K Singal, N. Khaper, V. Palace, and D. Kumar The role of oxidative stress in the genesis of heart disease Cardiovasc Res, December 1, 1998; 40(3): 426 - 432. [Abstract] [Full Text] [PDF]
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M. M. Kockx Apoptosis in the Atherosclerotic Plaque : Quantitative and Qualitative Aspects Arterioscler Thromb Vasc Biol, October 1, 1998; 18(10): 1519 - 1522. [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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A. W. Girotti Lipid hydroperoxide generation, turnover, and effector action in biological systems J. Lipid Res., August 1, 1998; 39(8): 1529 - 1542. [Abstract] [Full Text]
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A. Haunstetter and S. Izumo Apoptosis : Basic Mechanisms and Implications for Cardiovascular Disease Circ. Res., June 15, 1998; 82(11): 1111 - 1129. [Full Text] [PDF]
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 R. S. Rosenson and C. C. Tangney Antiatherothrombotic Properties of Statins: Implications for Cardiovascular Event Reduction JAMA, May 27, 1998; 279(20): 1643 - 1650. [Abstract] [Full Text] [PDF]
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M. Harada-Shiba, M. Kinoshita, H. Kamido, and K. Shimokado Oxidized Low Density Lipoprotein Induces Apoptosis in Cultured Human Umbilical Vein Endothelial Cells by Common and Unique Mechanisms J. Biol. Chem., April 17, 1998; 273(16): 9681 - 9687. [Abstract] [Full Text] [PDF]
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H. Wang and J. A. Keiser Molecular characterization of rabbit CPP32 and its function in vascular smooth muscle cell apoptosis Am J Physiol Heart Circ Physiol, April 1, 1998; 274(4): H1132 - H1140. [Abstract] [Full Text] [PDF]
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S. Dimmeler, V. Rippmann, U. Weiland, J. Haendeler, and A. M. Zeiher Angiotensin II Induces Apoptosis of Human Endothelial Cells : Protective Effect of Nitric Oxide Circ. Res., December 19, 1997; 81(6): 970 - 976. [Abstract] [Full Text]
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C. Hermann, A. M. Zeiher, and S. Dimmeler Shear Stress Inhibits H2O2-Induced Apoptosis of Human Endothelial Cells by Modulation of the Glutathione Redox Cycle and Nitric Oxide Synthase Arterioscler Thromb Vasc Biol, December 1, 1997; 17(12): 3588 - 3592. [Abstract] [Full Text]
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K. J. Scheidegger, R. W. James, and P. Delafontaine Differential Effects of Low Density Lipoproteins on Insulin-like Growth Factor-1 (IGF-1) and IGF-1 Receptor Expression in Vascular Smooth Muscle Cells J. Biol. Chem., August 25, 2000; 275(35): 26864 - 26869. [Abstract] [Full Text] [PDF]
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C. Zhang, Y. Cai, M. T. Adachi, S. Oshiro, T. Aso, R. J. Kaufman, and S. Kitajima Homocysteine Induces Programmed Cell Death in Human Vascular Endothelial Cells through Activation of the Unfolded Protein Response J. Biol. Chem., September 14, 2001; 276(38): 35867 - 35874. [Abstract] [Full Text] [PDF]
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J. Hoffmann, J. Haendeler, A. M. Zeiher, and S. Dimmeler TNFalpha and oxLDL Reduce Protein S-Nitrosylation in Endothelial Cells J. Biol. Chem., October 26, 2001; 276(44): 41383 - 41387. [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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