(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
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Abstract |
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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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Introduction |
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Experiments in animals that have demonstrated increased endothelial cell turnover rates in lesion-prone regions in the arterial tree1 2 support the hypothesis that injury to the endothelium might precipitate the atherosclerotic process.3 oxLDL is believed to play a key role as a triggering molecule in the earliest phase of atherosclerosis.4 The results of in vitro studies have shown that oxidatively modified LDL causes injury to endothelial cells.5 However, the mechanisms by which oxLDL injures endothelial cells are entirely unknown.
Endothelial cell injury may lead to two distinct types of cell death: apoptosis or necrosis.6 Apoptosis refers to the morphological alterations exhibited by "actively" dying cells, including cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation,7 whereas necrosis is characterized by cellular swelling, rupture of plasma membrane, and cell lysis.6 The signal transduction leading to apoptosis is characterized by a complex array of biochemical pathways, whereby CPP32, a member of the interleukin-1ß–converting enzyme–like protease family, appears to play a central role.8 9
It was the aim of the present study to investigate whether oxLDL induces apoptosis of endothelial cells via activation of CPP32-like proteases. Furthermore, we addressed any potentially protective effect of antioxidants on oxLDL-induced apoptosis as well as CPP32-like protease activity.
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Methods |
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Preparation and Oxidation of LDL
Human LDL was isolated through sequential ultracentrifugation and oxidated as described previously.10 Antioxidant-free LDL (0.3 mg protein/mL) was incubated with CuSO4 (5 µmol/L) for 24 hours at 23°C. The degree of oxidation was assessed via two different methods: the increase of mobility on agarose gel (1.4 versus native LDL) and the formation of thiobarbituric acid–reactive substances (3.4±0.8 mmol/L).
DNA Fragmentation
HUVEC were purchased from Cell Systems/Clonetics and cultured in
endothelial basal medium supplemented with
hydrocortisone (1 µg/mL), bovine brain extract (12 µg/mL),
gentamicin (50 µg/mL), amphotericin B (50 ng/mL), epidermal growth
factor (10 ng/mL), and 10% fetal calf serum (GIBCO) until the third
passage. DNA fragmentation analysis was carried out as recently
described11 12 with a cell death detection assay
(Boehringer-Mannheim Biochemicals). For demonstration of the
DNA ladder, 1x106 cells were removed from culture flask,
washed with PBS, and incubated in lysis buffer (5 mmol/L Tris-HCl,
pH 8, 20 mmol/L EDTA, and 0.5% Triton X-100) for 15 minutes at
4°C, and the DNA was isolated and radioactively labeled as previously
described.11 12 LDH was measured as previously
described.13
Measurement of CPP32-Like Protease Activity
HUVEC (5x105 cells) were lysed in buffer (1%
Triton X-100, 0.32 mol/L sucrose, 5 mmol/L EDTA, 1 mmol/L
phenylmethylsulfonyl fluoride, 10 µg/mL aprotinin, 10 µg/mL
leupeptin, 2 mmol/L dithiothreitol, and 10 mmol/L Tris-HCl,
pH 8) for 15 min at 4°C, followed by centrifugation
(20 000g, 10 minutes), and CPP32-like activity was measured
in resulting supernatants as described previously.8 9
Northern Blot
RNA was prepared according to the method of Liu et
al,14 and RNA was blotted onto nylon membranes; the blots
were hybridized with a radioactively labeled human CPP32 probe and
human GAPDH probe and incubated for 24 hours. Then, the blots were
washed (0.1% SDS/0.2% SSC) and exposed to x-ray films.
Western Blot
Proteins were prepared as described for detection of CPP32
activity, resolved on 15% SDS-polyacrylamide gels, and blotted
onto nitrocellulose membranes.11 12 CPP32/p17 was detected
through incubation with the primary antibody against human CPP32/p17
(Santa Cruz Biochemicals; 1:200 in BSA/0.5% Tween 20, for 1 hour) and
horseradish peroxidase–conjugated anti-goat IgG antibody (1:2000 in
BSA/0.5% Tween 20, for 1 hour), followed by enhanced chemiluminescence
(Amersham International).
Statistical Analysis
Statistical analysis was performed with ANOVA followed
by a modified Bonferroni LSD test (SPSS Software).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Induction of Apoptosis by oxLDL
Incubation of HUVEC with oxLDL for 18 hours induced DNA fragmentation in a concentration-dependent manner with maximal effects at 10 µg/mL (Fig 1
, top). In contrast, native LDL did
not induce apoptosis in the concentration range tested (Fig 1,
top). The induction of apoptosis by oxLDL was confirmed by
demonstrating DNA fragmentation through agarose gel electrophoresis
(data not shown). LDH release did not increase 
10 µg/mL oxLDL
(105±11% compared with control cells) excluding the induction of
necrosis.
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Involvement of CPP32-Like Proteases
Tumor necrosis factor-
as well as FAS-mediated
apoptosis is mediated via activation of CPP32-like
proteases.8 9 Therefore, we investigated the involvement
of CPP32-like proteases in oxLDL-stimulated apoptosis.
Incubation of HUVEC with oxLDL (10 µg/mL) significantly increased
CPP32-like protease activity (133±12% of controls), whereas native
LDL had no effect on CPP32-like protease activity (91±5%;
P<.05 versus oxLDL). Furthermore, inhibition of CPP32-like
activity by the specific tetrapeptide inhibitor Ac-DEVD-CHO
(100 µmol/L) completely prevented the oxLDL-induced
apoptosis (Fig 1
, bottom). Incubation of HUVEC with oxLDL (5 or
10 µg/mL) for 2 hours (data not shown) or 6 hours (Fig 2a) did not alter mRNA levels of CPP32, indicating the
lack of a transcriptional effect of oxLDL on CPP32. In contrast, oxLDL
incubation stimulated the proteolytic cleavage of CPP32 into its active
subunits, as demonstrated by the appearance of the CPP32 p17 subunit
(Fig 2b) and by a reduction in the full-length CPP32 of 44±9%
(mean±SEM; n=4).
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Inhibition of oxLDL-Induced Apoptosis by
Antioxidants
To investigate a potential involvement of oxidative stress in
apoptosis induction by oxLDL, we determined the effects of the
antioxidants NAC and the combination of vitamins C and E, which has
been shown to be more effective than the use of each vitamin
alone.12 NAC (200 µmol/L) as well as vitamins C and
E (10 µmol/L) prevented oxLDL-induced apoptosis (Fig 1,
bottom). Furthermore, the increase in CPP32-like protease activity
triggered by oxLDL (133±12% of control) was drastically reduced by
the antioxidants NAC (70±5.8% of control, P<.01) and
vitamins C and E (96±8% of control, P<.05). The decreased
CPP32-like protease activity correlated with a reduction in proteolytic
cleavage of the CPP32 into the active p17 subunit (Fig 2b).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of the present study demonstrate that oxLDL induces apoptosis of human endothelial cells via activation of a CPP32-like protease. Inhibition of proteolytical cleavage of CPP32 into its active subunits p12 and p17 completely abrogated oxLDL-induced apoptosis of HUVEC. These findings may provide a clue to the "response-to-injury" hypothesis of atherogenesis, which proposed an as-yet-undefined injury to the endothelium as the central mechanism for initiating atherosclerotic lesion development. Moreover, treatment of HUVEC with antioxidants prevented oxLDL-induced activation of CPP32 as well as apoptosis, suggesting that the generation of reactive oxygen species contributes to the induction of apoptosis by oxLDL.
Endothelial cells of lesion-prone regions are characterized by an increased cell turnover rate1 associated with an enhanced accumulation of LDL,2 suggesting a mechanistic link between endothelial cell injury and the susceptibility to atherosclerotic plaque development.3 oxLDL is a well-established triggering molecule in the atherosclerotic process.4 The present study demonstrates that even low concentrations of oxLDL activate a major signaling pathway, leading to endothelial cell apoptosis (ie, the proteolytical cleavage of CPP32-like proteases). CPP32, a member of the interleukin-1ß–converting enzyme–like protease family, has been identified as one of the key enzymes responsible for apoptosis in human cells.9 On activation, proteolytical cleavage of CPP32 releases two subunits to compose the active, mature form of the enzyme, with the larger p17 subunit containing the catalytic site.9 We now demonstrate that oxLDL-induced apoptosis is associated with enhanced CPP32-like protease activity due to increased proteolytic cleavage. Moreover, a specific peptide aldehyde inhibitor of CPP32 completely inhibited oxLDL-induced apoptosis. Taken together, these findings provide strong evidence to link oxLDL-induced apoptosis of HUVEC to the activation of CPP32. Thus, oxLDL appears to injure endothelial cells via activation of the cell suicide pathway.
The findings of the present study may provide a clue to the molecular mechanisms underlying the "response-to-injury" theory of atherogenesis. Apoptosis, which refers to the morphological alterations of "actively" dying cells in contrast to necrosis, is believed to represent an important defense in the event of questionable or irreparable cell damage.7 This type of physiological cell death, due to the use of an intrinsic mechanism that exists for the specific purpose of committing suicide, enables removal of unwanted cells without incitation of an inflammatory response, which usually follows cell death by necrosis. Thus, apoptosis of endothelial cells may allow for an uncompromised regeneration of the endothelial cell layer despite injurious insults. This is exactly what has been observed in lesion-prone areas of the arterial tree, which are characterized by an increased cell turnover rate.1
oxLDL has been shown to increase the endothelial production of partially reduced oxygen species, including hydrogen peroxide, superoxide anions, and hydroxyl radicals.10 15 The generation of reactive oxygen species has been demonstrated to be involved in mediating apoptosis via activation of the cell death program in numerous cells,16 including endothelial cells.12 Antioxidants completely prevented the induction of apoptosis in response to stimulation with oxLDL. Thus, the oxidant stress imposed by oxLDL appears to activate the signaling pathways, leading to apoptosis of endothelial cells. However, the precise mechanisms by which oxLDL activates CPP32-like activity and cleavage remain to be determined.
In summary, the present investigation demonstrates that oxLDL activates the suicide pathway leading to apoptosis of endothelial cells. The oxLDL-induced enhancement of CPP32-like protease activity appears to involve the elaboration of reactive oxygen species. These findings may not only provide a mechanistic clue to the "response-to-injury" hypothesis leading to increased cell turnover rates but also considerably extend the role of oxLDL as a key triggering molecule for activation of endothelial cells.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Deutsche Forschungsgemeinschaft (Di 600/2-1, Di 600/2-2, and Ga 431/2-1). We thank Christine Göbel for expert technical assistance.
Received February 3, 1997; revision received February 19, 1997; accepted February 20, 1997.
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 D. D. Bannerman and S. E. Goldblum Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis Am J Physiol Lung Cell Mol Physiol, June 1, 2003; 284(6): L899 - L914. [Abstract] [Full Text] [PDF]
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M. Artwohl, W. F. Graier, M. Roden, M. Bischof, A. Freudenthaler, W. Waldhausl, and S. M. Baumgartner-Parzer Diabetic LDL Triggers Apoptosis in Vascular Endothelial Cells Diabetes, May 1, 2003; 52(5): 1240 - 1247. [Abstract] [Full Text] [PDF]
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 M. Cnop, J. C. Hannaert, A. Y. Grupping, and D. G. Pipeleers Low Density Lipoprotein Can Cause Death of Islet {beta}-Cells by Its Cellular Uptake and Oxidative Modification Endocrinology, September 1, 2002; 143(9): 3449 - 3453. [Abstract] [Full Text] [PDF]
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G. Theilmeier, P. Verhamme, S. Dymarkowski, H. Beck, H. Bernar, M. Lox, S. Janssens, M.-C. Herregods, E. Verbeken, D. Collen, et al. Hypercholesterolemia in Minipigs Impairs Left Ventricular Response to Stress: Association With Decreased Coronary Flow Reserve and Reduced Capillary Density Circulation, August 27, 2002; 106(9): 1140 - 1146. [Abstract] [Full Text] [PDF]
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 S. Agrawal, M. L. Agarwal, M. Chatterjee-Kishore, G. R. Stark, and G. M. Chisolm Stat1-Dependent, p53-Independent Expression of p21waf1 Modulates Oxysterol-Induced Apoptosis Mol. Cell. Biol., April 1, 2002; 22(7): 1981 - 1992. [Abstract] [Full Text] [PDF]
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C. Napoli, F. de Nigris, J. S. Welch, F. B. Calara, R. O. Stuart, C. K. Glass, and W. Palinski Maternal Hypercholesterolemia During Pregnancy Promotes Early Atherogenesis in LDL Receptor-Deficient Mice and Alters Aortic Gene Expression Determined by Microarray Circulation, March 19, 2002; 105(11): 1360 - 1367. [Abstract] [Full Text] [PDF]
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 R. Locher, R. P. Brandes, W. Vetter, and M. Barton Native LDL Induces Proliferation of Human Vascular Smooth Muscle Cells via Redox-Mediated Activation of ERK 1/2 Mitogen-Activated Protein Kinases Hypertension, February 1, 2002; 39(2): 645 - 650. [Abstract] [Full Text] [PDF]
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S. R. Panini, L. Yang, A. E. Rusinol, M. S. Sinensky, J. V. Bonventre, and C. C. Leslie Arachidonate metabolism and the signaling pathway of induction of apoptosis by oxidized LDL/oxysterol J. Lipid Res., October 1, 2001; 42(10): 1678 - 1686. [Abstract] [Full Text] [PDF]
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W. Li, H. Dalen, J. W. Eaton, and X.-M. Yuan Apoptotic Death of Inflammatory Cells in Human Atheroma Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1124 - 1130. [Abstract] [Full Text] [PDF]
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Z. Guo, H. Van Remmen, H. Yang, X. Chen, J. Mele, J. Vijg, C. J. Epstein, Y.-S. Ho, and A. Richardson Changes in Expression of Antioxidant Enzymes Affect Cell-Mediated LDL Oxidation and Oxidized LDL-Induced Apoptosis in Mouse Aortic Cells Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1131 - 1138. [Abstract] [Full Text] [PDF]
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Z. Mallat and A. Tedgui Current Perspective on the Role of Apoptosis in Atherothrombotic Disease Circ. Res., May 25, 2001; 88(10): 998 - 1003. [Abstract] [Full Text] [PDF]
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E. Chavakis, E. Dernbach, C. Hermann, U. F. Mondorf, A. M. Zeiher, and S. Dimmeler Oxidized LDL Inhibits Vascular Endothelial Growth Factor-Induced Endothelial Cell Migration by an Inhibitory Effect on the Akt/Endothelial Nitric Oxide Synthase Pathway Circulation, April 24, 2001; 103(16): 2102 - 2107. [Abstract] [Full Text] [PDF]
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A. H. J. M. PIJPERS, P. A. V. SETTEN, L. P. W. J. V. D. HEUVEL, K. J. M. ASSMANN, H. B. P. M. DIJKMAN, A. H. M. PENNINGS, L. A. H. MONNENS, and V. W. M. V. HINSBERGH Verocytotoxin-Induced Apoptosis of Human Microvascular Endothelial Cells J. Am. Soc. Nephrol., April 1, 2001; 12(4): 767 - 778. [Abstract] [Full Text] [PDF]
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A. Pirillo, G. D. Norata, T. Zanelli, and A. L. Catapano Overexpression of Inducible Heat Shock Protein 70 in COS-1 Cells Fails to Protect From Cytotoxicity of Oxidized LDLs Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 348 - 354. [Abstract] [Full Text] [PDF]
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I. Spyridopoulos, J. Wischhusen, B. Rabenstein, P. Mayer, D. I. Axel, K.-U. Frohlich, and K. R. Karsch Alcohol Enhances Oxysterol-Induced Apoptosis in Human Endothelial Cells by a Calcium-Dependent Mechanism Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 439 - 444. [Abstract] [Full Text] [PDF]
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K. HEERMEIER, W. LEICHT, A. PALMETSHOFER, M. ULLRICH, C. WANNER, and J. GALLE Oxidized LDL Suppresses NF-{{kappa}}B and Overcomes Protection from Apoptosis in Activated Endothelial Cells J. Am. Soc. Nephrol., March 1, 2001; 12(3): 456 - 463. [Abstract] [Full Text]
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T.-S. Lee and L.-Y. Chau Fas/Fas ligand-mediated death pathway is involved in oxLDL-induced apoptosis in vascular smooth muscle cells Am J Physiol Cell Physiol, March 1, 2001; 280(3): C709 - C718. [Abstract] [Full Text] [PDF]
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 I. Kim, S.-O. Moon, C.-Y. Han, Y. K. Pak, S. K. Moon, J. J. Kim, and G. Y. Koh The angiopoietin-tie2 system in coronary artery endothelium prevents oxidized low-density lipoprotein-induced apoptosis Cardiovasc Res, March 1, 2001; 49(4): 872 - 881. [Abstract] [Full Text] [PDF]
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 L. Rossig, J. Haendeler, Z. Mallat, B. Hugel, J.-M. Freyssinet, A. Tedgui, S. Dimmeler, and A. M. Zeiher Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2081 - 2089. [Abstract] [Full Text] [PDF]
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 C. NAPOLI, O. QUEHENBERGER, F. DE NIGRIS, P. ABETE, C. K. GLASS, and W. PALINSKI Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells FASEB J, October 1, 2000; 14(13): 1996 - 2007. [Abstract] [Full Text]
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E. O. Harrington, A. Smeglin, N. Parks, J. Newton, and S. Rounds Adenosine induces endothelial apoptosis by activating protein tyrosine phosphatase: a possible role of p38alpha Am J Physiol Lung Cell Mol Physiol, October 1, 2000; 279(4): L733 - L742. [Abstract] [Full Text] [PDF]
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A. HEINLOTH, K. HEERMEIER, U. RAFF, C. WANNER, and J. GALLE Stimulation of NADPH Oxidase by Oxidized Low-Density Lipoprotein Induces Proliferation of Human Vascular Endothelial Cells J. Am. Soc. Nephrol., October 1, 2000; 11(10): 1819 - 1825. [Abstract] [Full Text]
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S. Dimmeler and A. M. Zeiher Endothelial Cell Apoptosis in Angiogenesis and Vessel Regression Circ. Res., September 15, 2000; 87(6): 434 - 439. [Abstract] [Full Text] [PDF]
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K. Irani Oxidant Signaling in Vascular Cell Growth, Death, and Survival : A Review of the Roles of Reactive Oxygen Species in Smooth Muscle and Endothelial Cell Mitogenic and Apoptotic Signaling Circ. Res., August 4, 2000; 87(3): 179 - 183. [Abstract] [Full Text] [PDF]
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G. H. Gibbons and M. J. Pollman Death Receptors, Intimal Disease, and Gene Therapy : Are Therapies That Modify Cell Fate Moving too Fas? Circ. Res., May 26, 2000; 86(10): 1009 - 1012. [Full Text] [PDF]
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D. Li and J. L. Mehta Upregulation of Endothelial Receptor for Oxidized LDL (LOX-1) by Oxidized LDL and Implications in Apoptosis of Human Coronary Artery Endothelial Cells : Evidence From Use of Antisense LOX-1 mRNA and Chemical Inhibitors Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 1116 - 1122. [Abstract] [Full Text] [PDF]
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A. E. Rusinol, L. Yang, D. Thewke, S. R. Panini, M. F. Kramer, and M. S. Sinensky Isolation of a Somatic Cell Mutant Resistant to the Induction of Apoptosis by Oxidized Low Density Lipoprotein J. Biol. Chem., March 15, 2000; 275(10): 7296 - 7303. [Abstract] [Full Text] [PDF]
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O. VIEIRA, I. ESCARGUEIL-BLANC, G. JÜRGENS, C. BORNER, L. ALMEIDA, R. SALVAYRE, and A. NÈGRE-SALVAYRE Oxidized LDLs alter the activity of the ubiquitin-proteasome pathway: potential role in oxidized LDL-induced apoptosis FASEB J, March 1, 2000; 14(3): 532 - 542. [Abstract] [Full Text]
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S. R. Thom, D. Fisher, Y. A. Xu, K. Notarfrancesco, and H. Ischiropoulos Adaptive responses and apoptosis in endothelial cells exposed to carbon monoxide PNAS, February 1, 2000; 97(3): 1305 - 1310. [Abstract] [Full Text] [PDF]
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M. M Kockx and A. G Herman Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res, February 1, 2000; 45(3): 736 - 746. [Abstract] [Full Text] [PDF]
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K. Walsh and J. M. Isner Apoptosis in inflammatory-fibroproliferative disorders of the vessel wall Cardiovasc Res, February 1, 2000; 45(3): 756 - 765. [Abstract] [Full Text] [PDF]
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 P Meerarani, P Ramadass, M. Toborek, H.-C. Bauer, H. Bauer, and B. Hennig Zinc protects against apoptosis of endothelial cells induced by linoleic acid and tumor necrosis factor {alpha}1 Am. J. Clinical Nutrition, January 1, 2000; 71(1): 81 - 87. [Abstract] [Full Text] [PDF]
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K. Hishikawa, B. S. Oemar, F. C. Tanner, T. Nakaki, T. Fujii, and T. F. Luscher Overexpression of Connective Tissue Growth Factor Gene Induces Apoptosis in Human Aortic Smooth Muscle Cells Circulation, November 16, 1999; 100(20): 2108 - 2112. [Abstract] [Full Text] [PDF]
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 J. Galle and K. Heermeier Angiotensin II and oxidized LDL: an unholy alliance creating oxidative stress Nephrol. Dial. Transplant., November 1, 1999; 14(11): 2585 - 2589. [Full Text] [PDF]
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R. C. M. Siow, J. P. Richards, K. C. Pedley, D. S. Leake, and G. E. Mann Vitamin C Protects Human Vascular Smooth Muscle Cells Against Apoptosis Induced by Moderately Oxidized LDL Containing High Levels of Lipid Hydroperoxides Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2387 - 2394. [Abstract] [Full Text] [PDF]
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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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