This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mallat, Z. Articles by Tedgui, A. Search for Related Content PubMed PubMed Citation Articles by Mallat, Z. Articles by Tedgui, A. Related Collections Apoptosis Pathophysiology Acute coronary syndromes

(Circulation Research. 2001;88:998.)
© 2001 American Heart Association, Inc.

Review

Current Perspective on the Role of Apoptosis in Atherothrombotic Disease

Ziad Mallat, Alain Tedgui

From Institut Fédératif de Recherche "Circulation Paris VII " and INSERM U541, Hôpital Lariboisière, Paris, France.

	Abstract

Top Abstract Introduction Occurrence of Apoptotic Death... Procoagulant Potential of... Apoptosis as an Important... Apoptosis as a Contributor... Clinical Implications References

 
Abstract—Thrombus formation on a disrupted atherosclerotic plaque is a threatening event that leads to vessel occlusion and acute ischemia. In this current perspective, we present evidence for apoptosis as a major determinant of the thrombogenicity of the plaque lipid core and a potential contributor to plaque erosion and associated thrombosis. Moreover, apoptosis may directly affect blood thrombogenicity through the release of apoptotic cells and microparticles into the bloodstream.

Key Words: apoptosis • thrombosis • atherosclerosis • acute coronary syndromes

	Introduction

Top Abstract Introduction Occurrence of Apoptotic Death... Procoagulant Potential of... Apoptosis as an Important... Apoptosis as a Contributor... Clinical Implications References

 
Acute ischemic syndromes (ie, unstable angina, myocardial infarction, and stroke) are severe clinical manifestations of atherosclerotic disease and account for most of the morbidity and mortality of atherosclerosis. They are primarily related to occlusion of the main vessel lumen by a thrombus formed on the contact of disrupted atherosclerotic plaques.¹ The thrombus, or part of it, eventually embolizes into the microvasculature, leading to disseminated microvascular obstruction.² Whatever the mechanism of plaque disruption (ie, deep rupture or superficial erosion), thrombus formation is the most threatening event. Therefore, identification of the pathophysiological mechanisms involved in plaque thrombogenicity is critical to our understanding of these clinical manifestations and may open the way to the elaboration of novel therapeutic strategies to prevent these serious events. The potential beneficial or detrimental roles of apoptotic death in plaque development have been recently reviewed in the literature.³ In this study, we present evidence for an etiological role of apoptosis as a contributor to thrombus formation and embolization leading to acute ischemic syndromes.

	Occurrence of Apoptotic Death in Atherosclerotic Disease

Top Abstract Introduction Occurrence of Apoptotic Death... Procoagulant Potential of... Apoptosis as an Important... Apoptosis as a Contributor... Clinical Implications References

 
Apoptosis is a major event occurring during atherosclerotic plaque development.^{4 5} All cell types are involved, with a high predominance of apoptotic macrophages.⁵ The distribution of apoptosis is heterogeneous within the plaque, being more frequent in regions rich in inflammatory cells and proinflammatory cytokines and much less abundant in regions characterized by a significant production of anti-inflammatory cytokines.⁶ This close association between apoptosis and inflammation suggests that regions of plaque disruption, which are known to be inflammatory, may expose a high percentage of apoptotic cells and apoptotic debris to the circulating blood.

Apoptosis is widely recognized as a clean death. Apoptotic cells and bodies are recognized by adjacent professional and nonprofessional phagocytes and are rapidly removed from the tissue without inducing an inflammatory response.⁷ However, this dogma was recently challenged by studies showing Fas-mediated activation of several proinflammatory genes during the apoptotic process.^{8 9} In addition, with regard to atherosclerotic plaques, recent in vitro studies suggest that removal of apoptotic cells may be inefficient in such a complex tissue. Indeed, oxidized phospholipids, as well as antibodies directed against them, which are abundant in advanced plaques, affect recognition of apoptotic or damaged cells by macrophages.¹⁰ Therefore, it is likely that the capacities of clearance of apoptotic cells are reduced in foam macrophages that are in an oxidation-rich environment. This would lead to the persistence within the plaque of apoptotic bodies with potentially high immunogenic properties.¹¹ Moreover, in some circumstances apoptotic cells are prone to undergo secondary necrosis,^{12 13 14} and this may lead to accumulation of extracellular lipids and to perpetuation of the inflammatory response. Besides these potential immunoinflammatory effects, we believe that one of the major roles of apoptosis in atherosclerosis is related to its high procoagulant potential.

	Procoagulant Potential of Apoptotic Cells and Microparticles

Top Abstract Introduction Occurrence of Apoptotic Death... Procoagulant Potential of... Apoptosis as an Important... Apoptosis as a Contributor... Clinical Implications References

 
The occurrence of phosphatidylserine (PS) in the exoplasmic leaflet of the plasma membrane is considered one of the hallmarks of cells undergoing apoptosis and more generally constitutes one of the determinants for the phagocytosis of apoptotic cells to be rapidly cleared.⁷ Once accessible, PS acquires a procoagulant potential, owing to its ability to promote the surface assembly and the catalytic efficiency of the characteristic enzyme complexes of the blood coagulation cascade,¹⁵ including the tissue factor (TF)/factor VIIa complex.¹⁶ This parallels PS externalization in activated platelets, which constitutes the basis of the platelet coagulant response.

PS exposure at the surface of apoptotic lymphocytic, monocytic, smooth muscle, or endothelial cells can induce procoagulant responses.^{17 18 19 20} Flynn et al¹⁹ have shown a thrombin-generating potential of vascular smooth muscle cells derived from human coronary atherosclerotic plaques that undergo apoptosis spontaneously in vitro. The thrombin-generating capacity was secondary to PS exposure.¹⁹ Other studies suggest that endothelial cells that cover the atherosclerotic plaques may also become procoagulant after apoptosis induction. Bombeli et al¹⁸ have shown that apoptotic human umbilical vein endothelial cells (HUVECs) become procoagulant by increased expression of PS and loss of anticoagulant membrane components, including thrombomodulin, heparan sulfates, and TF pathway inhibitor. Moreover, these authors reported a marked increase in the binding of nonactivated platelet to apoptotic HUVECs.²¹ Taken together, these data provide evidence that cells undergoing apoptosis, whatever their origin, may contribute to thrombotic events.

Interestingly, PS-dependent procoagulant activities are also detectable in the supernatant of various apoptotic or stimulated cells.¹⁷ The supernatant procoagulant activities are clearly related to the degree of apoptosis in cultured cells and are accounted for by the release of microparticles, probably stemming from surface blebs of apoptotic cells.^{17 22} These procoagulant activities are not different from those of microparticles shed from activated, nonapoptotic cells or platelets.^{20 23 24} These in vitro observations strongly suggest that apoptotic cells and microparticles may play an important role in the initiation or perpetuation of thrombotic states in vivo.

	Apoptosis as an Important Determinant of Plaque Thrombogenicity

Top Abstract Introduction Occurrence of Apoptotic Death... Procoagulant Potential of... Apoptosis as an Important... Apoptosis as a Contributor... Clinical Implications References

 
Thrombogenicity of the Ruptured Atherosclerotic Plaque
Pathological and functional studies have identified cellular and extracellular TF as a major determinant of the thrombogenicity of the plaque lipid core.^{25 26} TF is a 47-kDa transmembrane glycoprotein that initiates blood coagulation by binding the coagulation factor VII and its activated form (factor VIIa) to form a high-affinity complex. This binary complex proteolytically activates factors IX and X, which in turn leads to thrombin generation.²⁷ Thrombin generation will, in turn, activate platelets, induce TF, and activate coagulation factors more proximal in the cascade. The overlying thrombus is extremely thrombogenic, and in the vast majority of cases (85%), it is rich in fibrin.²⁸ TF activity is significantly higher in plaque from patients with unstable angina and myocardial infarction than in that from patients with stable angina.²⁹ TF activity is mainly localized in the lipid-rich atheromatous core and is directly related to the thrombogenicity of the plaque material.²⁵ Moreover, specific inhibition of vascular TF by the use of recombinant TF pathway inhibitor is associated with a significant reduction of acute thrombus formation²⁶ in lipid-rich plaques. These findings underscore the critical role of the extrinsic coagulation pathway in the generation of acute ischemic syndromes but do not provide any mechanistic explanation for the enhanced TF activity of the plaque lipid core.

TF is operational on the surface of cell membranes, and it is known that its activity is highly dependent on the presence of anionic phospholipids, chiefly PS.¹⁶ Because apoptosis is associated with significant PS exposure on the cell surface and leads to the shedding of PS-containing membrane microparticles, we hypothesized that apoptosis may be directly responsible for TF activation within the plaque. By use of immunohistochemical techniques, we found a colocalization between TF expression (cellular and extracellular) and apoptotic death, particularly in the lipid core, suggesting that TF may be released in apoptotic microparticles during cell death.³⁰ This was confirmed by isolating shed membrane microparticles from the lipid core of plaques. Quantification of the microparticles by use of a prothrombinase assay revealed significantly higher levels of PS- and TF-containing microparticles in plaque supernatants compared with extracts of normal arteries. In addition, we found that these plaque-derived apoptotic microparticles account for almost all TF activity of the plaque extracts, indicating a direct causal relationship between their presence and TF activity.³⁰ Although we do not exclude a contribution from other cell types present in the plaque,^{31 32} we have found that most of the microparticles originated from macrophages and lymphocytes that are known to be abundant at sites of plaque rupture.³³ These results suggest that shed membrane apoptotic microparticles play a major role in the initiation of the coagulation cascade after plaque rupture and exposure of the lipid core to the circulating blood. The recent findings that macrophage apoptotic death is significantly increased at sites of plaque rupture and thrombosis in patients with sudden coronary death³⁴ and that apoptosis is significantly increased in unstable versus stable human plaques³⁵ strongly support our hypothesis.

Thrombogenicity of the Eroded Atherosclerotic Plaque
Plaque rupture of a thin fibrous cap overlying a lipid core is not necessarily the only final common pathway in the formation of coronary thrombi. Virmani and colleagues^{36 37} recently reported several consistent studies showing that plaque erosion without rupture is an important predisposing substrate for acute coronary syndromes (ACSs) and sudden cardiac death. Although risk factors predisposing to plaque erosion have been identified,^{36 37} the cellular and molecular mechanisms responsible for this process remain unknown. We hypothesized that apoptosis of luminal endothelial cells may be one of the mechanisms leading to erosion and thrombosis.

Vascular endothelial cells are continuously exposed to a range of hemodynamic forces that have a great impact on their cellular structure and function. HUVECs cultured under static conditions undergo a basal low level of apoptosis, whereas exposure to flow inhibits the apoptotic process.³⁸ Using carotid human atherosclerotic plaques, we recently found that blood flow exerts a direct influence on endothelial cell survival in human atherosclerosis.³⁹ Analysis of longitudinal plaque sections revealed the presence of luminal endothelial cell apoptosis in 60% of plaques examined. Interestingly, luminal endothelial cell apoptosis in these nonruptured plaques occurred preferentially in the downstream parts of the plaques where low shear prevails in comparison with the upstream parts.³⁹ The increase in apoptosis was not balanced by an increase in cell proliferation, suggesting that relatively large areas of endothelial erosion may occur in the distal part of atherosclerotic plaques as a consequence of endothelial apoptosis. This is supported by ultrastructural studies showing frequent endothelial denudation⁴⁰ or accelerated endothelial senescence in regions of disturbed flow located downstream from the stenosis.⁴¹ Given the high procoagulant and proadhesive potentials of apoptotic endothelial cells (see above) and the propensity of denuded vessel segments to increased vasospasm and platelet aggregation, primary endothelial cell apoptosis and secondary denudation in regions of low or disturbed flow may lead to lumen thrombosis favoring plaque progression or occurrence of ACS. Interestingly, Ledru et al⁴² recently examined geometric features of coronary artery lesions favoring acute occlusion and myocardial infarction. They found that a steep outflow angle of a stenosis, which is a feature characteristic of disturbed flow downstream from the stenosis, is an independent predictor of infarction at 3-year follow-up.

Farb et al³⁶ found that the amount of fibrin and platelets within thrombi formed on the contact of eroded plaques was similar to that in thrombi formed on the contact of ruptured plaques. Nearly 40% of thrombi formed on eroded plaques were predominantly composed of fibrin, which means that early fibrin deposition is present in the absence of plaque rupture. This finding is intriguing, because thrombi that usually develop on subendothelial collagen after superficial endothelial denudation are known to be predominantly, if not exclusively, composed of platelets. Therefore, we believe, like others,⁴³ that early deposition of a significant amount of fibrin in superficially eroded plaques involves the TF-dependent extrinsic pathway of coagulation. This process may be better explained if one considers the role of TF-bearing apoptotic endothelial cells and microparticles in the pathophysiology of plaque erosion and thrombosis. This interesting hypothesis deserves to be tested in future experimental studies.

Despite this large body of evidence for a prothrombogenic role of apoptosis in vascular disease, recent experimental models in which massive apoptosis was induced within the vessel did not mention the occurrence of thrombosis.^{9 44} This seems at odds with our hypothesis. However, it is noteworthy that apoptotic death was specifically induced in neointimal smooth muscle cells of nonruptured plaques through seeding of vascular smooth muscle cells overexpressing the Fas-associated death domain or through downregulation of intimal cell bcl-x_L expression with the use of antisense oligonucleotides.^{9 44} Endothelial cells were not reported to be apoptotic in these models.^{9 44} Because there was no direct contact between apoptotic cells and the circulating blood, the absence of thrombosis is not surprising in these experimental conditions.

	Apoptosis as a Contributor to Blood Thrombogenicity

Top Abstract Introduction Occurrence of Apoptotic Death... Procoagulant Potential of... Apoptosis as an Important... Apoptosis as a Contributor... Clinical Implications References

 
Besides the classic paradigm that coagulation is triggered after exposure of vessel-wall TF to the circulating blood after vessel damage, there is recent evidence that acute thrombosis may be initiated by TF originating from the circulating blood.⁴⁵ Giesen et al⁴⁵ have elegantly shown a TF-dependent fibrin-rich thrombus formation on pig arterial media (which contains no stainable TF) and on collagen-coated glass slides (devoid of TF) after exposure of these surfaces to flowing native human blood. Active TF was isolated from freshly collected whole blood and was shown to originate mainly from circulating leukocytes. These cells are thought to be activated, at least at the time of thrombus formation, leading to deencryption of the cell-surface TF. Indeed, within the thrombus, TF was shown to be released in vesicular structures and can be transferred from leukocytes to platelet membranes through CD15 and TF-mediated interactions,⁴⁶ potentially leading to the formation of TF-platelet hybrids, a phenomenon that would be critical to thrombus propagation.⁴⁵

In addition to activated leukocytes, we believe that apoptosis may also markedly contribute to the shedding of TF-bearing vesicles and hence to the thrombogenicity of the circulating blood. Apoptotic cells are the prototype of cells that can embolize into the circulation. Among the first morphological changes after initiation of the apoptotic process are membrane blebbing with shedding of microparticles, loss of focal adhesion sites, and retraction from the matrix followed by detachment.⁴⁷ After plaque rupture and exposure of the plaque gruel, all vessel wall constituents, including TF-bearing apoptotic cells and microparticles, if present, can embolize into the circulation.² Also, even in the absence of plaque rupture, luminal endothelial cells undergoing apoptosis,³⁹ which may have already attracted activated platelets and fibrin, will finally detach and embolize into the circulating blood. Moreover, a proportion of viable endothelial cells that have detached from the extracellular matrix may become apoptotic,^{48 49} probably because of the loss of contact with antiapoptotic components of the vessel wall.⁴⁷ If true, all these apoptotic cells and microparticles will eventually circulate in the peripheral blood and, in concert with activated cells and platelets,^{50 51} will participate in the dissemination of the procoagulant potential, contributing to blood thrombogenicity.

Several lines of evidence support the hypothesis that embolization of apoptotic or activated cells and microparticles may play a significant role in blood thrombogenicity. Recently, we examined the peripheral blood of coronary and noncoronary patients for the presence of circulating PS-bearing microparticles. Patients with ACS had a significant increase in circulating microparticles compared with stable coronary patients.⁵² Structurally, these microparticles resemble those extracted from human atherosclerotic plaques, but their tissue origin is presently unknown. A significant proportion of the microparticles was of endothelial or platelet origin. This may reflect the endothelial erosion at the site of plaque disruption, the endothelial injury on exposure of plaque microvessels to inflammatory cells, or the injury associated with myocardial ischemia. Yet the importance of each of these potential factors is unknown. Patients with ACS have elevated levels of circulating TF,⁵³ and there is evidence that acute thrombosis may be initiated by membrane-bound circulating TF originating from activated or injured cells.⁴⁵ We believe that a major source of blood-borne TF could be the circulating microparticles that are endowed with potent procoagulant potential attributable to the presence of PS at their surface. A significant increase in the number of circulating endothelial cells, some of them being apoptotic,⁴⁹ has also been reported in patients with ACS.⁴⁸ These circulating cells and carcasses could represent those cells that have desquamated from the basal membrane in the early stages of apoptosis and that will engage into an apoptotic process once in the bloodstream. Taken together, these findings from different groups highlight the potential role of cell injury and apoptosis and the shedding of circulating microparticles in the pathophysiology of ACS. It is noteworthy that systemic disorders or conditions characterized by increased rate of apoptosis or increased circulating apoptotic microparticles^{54 55 56 57} (ie, disseminated lupus erythematosus, antiphospholipid syndrome, and cocaine abuse) are important risk factors for coronary thrombosis. The circulating procoagulant microparticles may also contribute to blood thrombogenicity of patients with hyperlipidemia or high blood glucose concentrations; these vascular risk factors are known to be responsible for increased apoptotic activity in vitro.^{58 59 60}

In addition to their direct effect in promotion or amplification of the coagulation cascade, the circulating microparticles may also act in a variety of intercellular adhesion and activation processes and may participate in the long-range transmission of information to sites remote from the microenvironment of their formation.^{23 61 62 63} Circulating markers of inflammation are good predictors of vascular risk,⁶⁴ and ACS are associated with a systemic inflammatory reaction. The circulating microparticles might contribute to such alterations.

	Clinical Implications

Top Abstract Introduction Occurrence of Apoptotic Death... Procoagulant Potential of... Apoptosis as an Important... Apoptosis as a Contributor... Clinical Implications References

 
Thrombus formation on a disrupted atherosclerotic plaque is the major threatening event in atherosclerotic disease. There is a growing body of evidence suggesting that apoptosis, through its procoagulant and proadhesive potentials, may play a critical role in both plaque and blood thrombogenicity and may be an important step in the transition from stable to unstable atherosclerotic disease. The recognition of the importance of apoptosis in atherothrombotic disease may lead to the development of new diagnostic and prognostic markers in acute ischemic syndrome evaluation. Circulating apoptotic and nonapoptotic microparticles could be a valuable marker of thrombus formation and hence of the instability of the atherosclerotic plaque. This hypothesis is now being tested in a multicenter study. On the other hand, diagnostic techniques aiming at the detection of apoptotic death in vivo⁶⁵ may be of great value in the identification of unstable atherosclerotic plaques.

The recognition of the importance of apoptosis in atherothrombotic disease may also lead to the development of new antithrombotic strategies aiming at the reduction of apoptotic death.⁴⁷ In fact, many of the available therapeutic agents that have been shown to reduce the incidence or recurrence of ACS may have been active, at least in part, through reduction in apoptosis. Atherogenic lipoproteins have potent proapoptotic properties.⁵⁸ A reduction in atherogenic lipid accumulation within the plaque may greatly decrease the level of apoptotic death within the plaque, therefore limiting the formation of the thrombogenic lipid core. In support of this view, Kockx et al⁶⁶ recently observed a marked reduction in apoptosis in rabbit atherosclerotic lesions after 6 months of cholesterol withdrawal. Such a reduction in apoptosis may be an important mechanism of plaque stabilization after hypolipidemic drug therapy. Recently, angiotensin-converting enzyme inhibitors have been shown to significantly reduce the occurrence of myocardial infarction and stroke in humans.⁶⁷ We postulate that a reduction in endothelial apoptosis and thrombosis, through inhibition of the endothelial proapoptotic effects of angiotensin II,⁶⁸ might be one of the potential mechanisms responsible for this beneficial effect. Similarly, the beneficial atheroprotective effects of estradiol may result, at least in part, from the preservation of endothelial integrity and inhibition of endothelial cell apoptosis.⁶⁹ This may also be the case of vitamins with antioxidant properties that inhibit oxidized LDL–induced endothelial apoptosis in vitro.⁵⁸ Another powerful antioxidant and antiapoptotic product for many cell types, including endothelial cells, is the product of the heme oxygenase (HO)-1 gene.^{70 71} Deficiency in HO-1 is associated with severe endothelial damage,⁷² whereas upregulation of HO-1 is associated with expression of various cytoprotective genes, such as bcl-x_L, and prevents transplant arteriosclerosis.⁷¹ Moreover, endothelial integrity in this setting is associated with the expression of anti-inflammatory cytokines, including interleukin-10.⁷³

Finally, it should be kept in mind that the occurrence of apoptosis within human atherosclerotic plaques is highly dependent on the inflammatory balance.⁶ Therefore, in vivo (local) delivery of products with anti-inflammatory activity, such as interleukin-10, might be a sound strategy to deactivate inflammatory cells and reduce apoptotic death and its prothrombogenic properties, leading to plaque stabilization.

	Acknowledgments

 
This work was supported by Fondation pour la Recherche Médicale, Action Recherche Santé 2000, and by Fondation de France.

	Footnotes

 
Original received December 27, 2000; revision received March 19, 2001; accepted March 21, 2001.

Correspondance to Ziad Mallat, MD, PhD, INSERM U541, Hôpital Lariboisière, 41, Bd de la Chapelle, 75475 Paris, Cedex 10, France.

	References

Top Abstract Introduction Occurrence of Apoptotic Death... Procoagulant Potential of... Apoptosis as an Important... Apoptosis as a Contributor... Clinical Implications References

 
1. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250.[Medline] [Order article via Infotrieve]

2. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation. 2000;101:570–580.[Free Full Text]

3. Kockx MM, Herman AG. Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res. 2000;45:736–746.[Abstract/Free Full Text]

4. Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest. 1995;95:2266–2274.

5. Kockx MM. Apoptosis in the atherosclerotic plaque: quantitative and qualitative aspects. Arterioscler Thromb Vasc Biol. 1998;18:1519–1522.[Abstract/Free Full Text]

6. Mallat Z, Heymes C, Ohan J, Faggin E, Lesèche G, Tedgui A. Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. Arterioscler Thromb Vasc Biol. 1999;19:611–616.[Abstract/Free Full Text]

7. Fadok VA, Savill JS, Haslett C, Bratton DL, Doherty DE, Campbell PA, Henson PM. Different populations of macrophages use either the vitronectin receptor or the phosphatidylserine receptor to recognize and remove apoptotic cells. J Immunol. 1992;149:4029–4035.[Abstract]

8. Miwa K, Asano M, Horai R, Iwakura Y, Nagata S, Suda T. Caspase 1-independent IL-1ß release and inflammation induced by the apoptosis inducer Fas ligand. Nat Med. 1998;4:1287–1292.[Medline] [Order article via Infotrieve]

9. Schaub FJ, Han DK, Conrad Liles W, Adams LD, Coats SA, Ramachandran RK, Seifert RA, Schwartz SM, Bowen-Pope DF. Fas/FADD-mediated activation of a specific program of inflammatory gene expression in vascular smooth muscle cells. Nat Med. 2000;6:790–796.[Medline] [Order article via Infotrieve]

10. Chang MK, Bergmark C, Laurila A, Horkko S, Han KH, Friedman P, Dennis EA, Witztum JL. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc Natl Acad Sci U S A. 1999;96:6353–6358.[Abstract/Free Full Text]

11. Levine JS, Koh JS. The role of apoptosis in autoimmunity: immunogen, antigen, and accelerant. Semin Nephrol. 1999;19:34–47.[Medline] [Order article via Infotrieve]

12. Majno G, Joris I. Apoptosis, oncosis, and necrosis. Am J Pathol. 1995;146:3–15.[Abstract]

13. Savill J, Haslett C. Granulocyte clearance by apoptosis in the resolution of inflammation. Semin Cell Biol. 1995;6:385–393.[Medline] [Order article via Infotrieve]

14. Harper L, Ren Y, Savill J, Adu D, Savage CO. Antineutrophil cytoplasmic antibodies induce reactive oxygen-dependent dysregulation of primed neutrophil apoptosis and clearance by macrophages. Am J Pathol. 2000;157:211–220.[Abstract/Free Full Text]

15. Pei G, Powers DD, Lentz BR. Specific contribution of different phospholipid surfaces to the activation of prothrombin by the fully assembled prothrombinase. J Biol Chem. 1993;268:3226–3233.[Abstract/Free Full Text]

16. Bach R, Rifkin DB. Expression of tissue factor procoagulant activity: regulation by cytosolic calcium. Proc Natl Acad Sci U S A. 1990;87:6995–6999.[Abstract/Free Full Text]

17. Aupeix K, Hugel B, Martin T, Bischoff P, Lill H, Pasquali JL, Freyssinet JM. The significance of shed membrane particles during programmed cell death in vitro, and in vivo, in HIV-1 infection. J Clin Invest. 1997;99:1546–1554.[Medline] [Order article via Infotrieve]

18. Bombeli T, Karsan A, Tait JF, Harlan JM. Apoptotic vascular endothelial cells become procoagulant. Blood. 1997;89:2429–2442.[Abstract/Free Full Text]

19. Flynn PD, Byrne CD, Baglin TP, Weissberg PL, Bennett MR. Thrombin generation by apoptotic vascular smooth muscle cells. Blood. 1997;89:4378–4384.[Abstract/Free Full Text]

20. Aupeix K, Toti F, Satta N, Bischoff P, Freyssinet JM. Oxysterols induce membrane procoagulant activity in monocytic THP-1 cells. Biochem J. 1996;314:1027–1033.

21. Bombeli T, Schwartz BR, Harlan JM. Endothelial cells undergoing apoptosis become proadhesive for nonactivated platelets. Blood. 1999;93:3831–3838.[Abstract/Free Full Text]

22. Zhang J, Driscoll TA, Hannun YA, Obeid LM. Regulation of membrane release in apoptosis. Biochem J. 1998;334:479–485.

23. Satta N, Toti F, Feugeas O, Bohbot A, Dachary-Prigent J, Eschwège V, Hedman H, Freyssinet JM. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J Immunol. 1994;153:3245–3255.[Abstract]

24. Zwaal RF, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood. 1997;89:1121–1132.[Free Full Text]

25. Toschi V, Gallo G, Lettino M, Fallon JT, Gertz SD, Fernandez-Ortiz A, Cheserbo JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ. Tissue factor modulates thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95:594–599.[Abstract/Free Full Text]

26. Badimon JJ, Lettino M, Toschi V, Fuster V, Berrozpe M, Chesebro JH, Badimon L. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation. 1999;99:1780–1787.[Abstract/Free Full Text]

27. Pike AC, Brzozowski AM, Roberts SM, Olsen OH, Persson E. Structure of human factor VIIa and its implications for the triggering of blood coagulation. Proc Natl Acad Sci U S A. 1999;96:8925–8930.[Abstract/Free Full Text]

28. Rentrop KP. Thrombi in acute coronary syndromes: revisited and revised. Circulation. 2000;101:1619–1626.[Free Full Text]

29. Ardissino D, Merlini PA, Ariens R, Coppola R, Bramucci E, Mannucci PM. Tissue-factor antigen and activity in human coronary atherosclerotic plaques. Lancet. 1997;349:769–771.[Medline] [Order article via Infotrieve]

30. Mallat Z, Hugel B, Ohan J, Lesèche G, Freyssinet JM, Tedgui A. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation. 1999;99:348–353.[Abstract/Free Full Text]

31. Schecter AD, Spirn B, Rossikhina M, Giesen PL, Bogdanov V, Fallon JT, Fisher EA, Schnapp LM, Nemerson Y, Taubman MB. Release of active tissue factor by human arterial smooth muscle cells. Circ Res. 2000;87:126–132.[Abstract/Free Full Text]

32. Tedgui A, Mallat Z. Smooth muscle cells: another source of tissue factor-containing microparticles in atherothrombosis? Circ Res. 2000;87:81–82.[Free Full Text]

33. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;89:36–44.[Abstract/Free Full Text]

34. Kolodgie FD, Narula J, Burke AP, Haider N, Farb A, Hui-Liang Y, Smialek J, Virmani R. Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol. 2000;157:1259–1268.[Abstract/Free Full Text]

35. Bauriedel G, Hutter R, Welsch U, Bach R, Sievert H, Luderitz B. Role of smooth muscle cell death in advanced coronary primary lesions: implications for plaque instability. Cardiovasc Res. 1999;41:480–488.[Abstract/Free Full Text]

36. Farb A, Burke AP, Tang AL, Liang YH, Mannan P, Smialek J, Virmani R. Coronary plaque erosion without rupture into a lipid core: a frequent cause of coronary thrombosis in sudden coronary death. Circulation. 1996;93:1354–1363.[Abstract/Free Full Text]

37. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:1276–1282.[Abstract/Free Full Text]

38. Dimmeler S, Haendeler J, Rippmann V, Nehls M, Zeiher AM. Shear stress inhibits apoptosis of human endothelial cells. FEBS Lett. 1996;399:71–74.[Medline] [Order article via Infotrieve]

39. Tricot O, Mallat Z, Heymes C, Belmin J, Lesèche G, Tedgui A. Relation between endothelial cell apoptosis and blood flow direction in human atherosclerotic plaques. Circulation. 2000;101:2450–2453.[Abstract/Free Full Text]

40. Constantinides P, Harkey M. Electron microscopic exploration of human endothelium in step-serial sections of early and advanced atherosclerotic lesions. Ann N Y Acad Sci. 1990;598:113–124.[Medline] [Order article via Infotrieve]

41. Burrig KF. The endothelium of advanced atherosclerotic plaques in humans. Arterioscler Thromb. 1991;11:1678–1689.[Abstract/Free Full Text]

42. Ledru F, Theroux P, Lesperance J, Laurier J, Ducimetiere P, Guermonprez JL, Diebold B, Blanchard D. Geometric features of coronary artery lesions favoring acute occlusion and myocardial infarction: a quantitative angiographic study. J Am Coll Cardiol. 1999;33:1353–1361.[Abstract/Free Full Text]

43. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262–1275.[Free Full Text]

44. Pollman MJ, Hall JL, Mann MJ, Zhang L, Gibbons GH. Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease. Nat Med. 1998;4:222–227.[Medline] [Order article via Infotrieve]

45. Giesen PL, Rauch U, Bohrmann B, Kling D, Roque M, Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A. 1999;96:2311–2315.[Abstract/Free Full Text]

46. Rauch U, Bonderman D, Bohrmann B, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. Blood. 2000;96:170–175.[Abstract/Free Full Text]

47. Mallat Z, Tedgui A. Apoptosis in the vasculature: mechanisms and functional importance. Br J Pharmacol. 2000;130:947–962.[Medline] [Order article via Infotrieve]

48. Mutin M, Canavy I, Blann A, Bory M, Sampol J, Dignat-George F. Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood. 1999;93:2951–2958.[Abstract/Free Full Text]

49. Dignat-George F, Blann A, Sampol J. Circulating endothelial cells in acute coronary syndromes [letter]. Blood. 2000;95:728.[Free Full Text]

50. Jude B, Agraou B, Mcfadden EP, Susen S, Bauters C, Lepelley P, Vanhaesbroucke C, Devos P, Cosson A, Asseman P. Evidence for time-dependent activation of monocytes in the systemic circulation in unstable angina but not in acute myocardial infarction or in stable angina. Circulation. 1994;90:1662–1668.[Abstract/Free Full Text]

51. Gawaz M, Neumann FJ, Ott I, Schiessler A, Schomig A. Platelet function in acute myocardial infarction treated with direct angioplasty. Circulation. 1996;93:229–237.[Abstract/Free Full Text]

52. Mallat Z, Benamer H, Hugel B, Benessiano J, Steg PG, Freyssinet JM, Tedgui A. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation. 2000;101:841–843.[Abstract/Free Full Text]

53. Soejima H, Ogawa H, Yasue H, Kaikita K, Nishiyama K, Misumi K, Takazoe K, Miyao Y, Yoshimura M, Kugiyama K, Nakamura S, Tsuji I, Kumeda K. Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation. 1999;99:2908–2913.[Abstract/Free Full Text]

54. Casciola-Rosen LA, Rosen A, Petri M, Schlissel M. Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: implications for coagulation events and antigenic spread in systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1996;93:1624–1629.[Abstract/Free Full Text]

55. Bordron A, Dueymes M, Levy Y, Jamin C, Leroy JP, Piette JC, Shoenfeld Y, Youinou PY. The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis. J Clin Invest. 1998;101:2029–2035.[Medline] [Order article via Infotrieve]

56. Combes V, Simon AC, Grau GE, Arnoux D, Camoin L, Sabatier F, Mutin M, Sanmarco M, Sampol J, Dignat-George F. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest. 1999;104:93–102.[Medline] [Order article via Infotrieve]

57. He J, Xiao Y, Zhang L. Cocaine induces apoptosis in human coronary artery endothelial cells. J Cardiovasc Pharmacol. 2000;35:572–580.[Medline] [Order article via Infotrieve]

58. Dimmeler S, Haendeler J, Galle J, Zeiher AM. 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. Circulation. 1997;95:1760–1763.[Abstract/Free Full Text]

59. Baumgartner-Parzer SM, Wagner L, Pettermann M, Grillari J, Gessl A, Waldhausl W. High-glucose–triggered apoptosis in cultured endothelial cells. Diabetes. 1995;44:1323–1327.[Abstract]

60. Min C, Kang E, Yu SH, Shinn SH, Kim YS. Advanced glycation end products induce apoptosis and procoagulant activity in cultured human umbilical vein endothelial cells. Diabetes Res Clin Pract. 1999;46:197–202.[Medline] [Order article via Infotrieve]

61. Barry OP, Praticò D, Lawson JA, FitzGerald GA. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J Clin Invest. 1997;99:2118–2127.[Medline] [Order article via Infotrieve]

62. Freyssinet JM, Toti F, Hugel B, Gidon-Jeangirard C, Kunzelmann C, Martinez MC, Meyer D. Apoptosis in vascular disease. Thromb Haemost. 1999;82:727–735.[Medline] [Order article via Infotrieve]

63. Fourcade O, Simon MF, Viode C, Rugani FL, Ragab A, Fournie B, Sarda L, Chap H. Secretory phospholipase A₂ generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell. 1995;80:919–927.[Medline] [Order article via Infotrieve]

64. Ridker PM. Inflammation, atherosclerosis, and cardiovascular risk: an epidemiologic view. Blood Coagul Fibrinolysis. 1999;10(suppl 1):S9–S12.

65. Blankenberg FG, Katsikis PD, Tait JF, Davis RE, Naumovski L, Ohtsuki K, Kopiwoda S, Abrams MJ, Darkes M, Robbins RC, Maecker HT, Strauss HW. In vivo detection and imaging of phosphatidylserine expression during programmed cell death. Proc Natl Acad Sci U S A. 1998;95:6349–6354.[Abstract/Free Full Text]

66. Kockx MM, De Meyer GR, Buyssens N, Knaapen MW, Bult H, Herman AG. Cell composition, replication, and apoptosis in atherosclerotic plaques after 6 months of cholesterol withdrawal. Circ Res. 1998;83:378–387.[Abstract/Free Full Text]

67. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–153. [Published erratum appears in N Engl J Med. 2000;342:748].[Abstract/Free Full Text]

68. Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM. Angiotensin II induces apoptosis of human endothelial cells: protective effect of nitric oxide. Circ Res. 1997;81:970–976.[Abstract/Free Full Text]

69. Spyridopoulos I, Sullivan AB, Kearney M, Isner JM, Losordo DW. Estrogen-receptor-mediated inhibition of human endothelial cell apoptosis: estradiol as a survival factor. Circulation. 1997;95:1505–1514.[Abstract/Free Full Text]

70. Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, Barrow RK, Tysoe SA, Wolosker H, Baranano DE, Dore S, Poss KD, Snyder SH. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol. 1999;1:152–157.[Medline] [Order article via Infotrieve]

71. Hancock WW, Buelow R, Sayegh MH, Turka LA. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes. Nat Med. 1998;4:1392–1396.[Medline] [Order article via Infotrieve]

72. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999;103:129–135.[Medline] [Order article via Infotrieve]

73. Bach FH, Ferran C, Hechenleitner P, Mark W, Koyamada N, Miyatake T, Winkler H, Badrichani A, Candinas D, Hancock WW. Accommodation of vascularized xenografts: expression of "protective genes" by donor endothelial cells in a host Th2 cytokine environment. Nat Med. 1997;3:196–204. [Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				M. Mayr, D. Grainger, U. Mayr, A. S. Leroyer, G. Leseche, A. Sidibe, O. Herbin, X. Yin, A. Gomes, B. Madhu, et al. Proteomics, Metabolomics, and Immunomics on Microparticles Derived From Human Atherosclerotic Plaques Circ Cardiovasc Genet, August 1, 2009; 2(4): 379 - 388. [Abstract] [Full Text] [PDF]

				W. L. Holland and S. A. Summers Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights from in Vivo Manipulation of Sphingolipid Metabolism Endocr. Rev., June 1, 2008; 29(4): 381 - 402. [Abstract] [Full Text] [PDF]

				J. J. Stampfuss, P. Censarek, D. Bein, K. Schror, M. Grandoch, C. Naber, and A.-A. Weber Membrane environment rather than tissue factor expression determines thrombin formation triggered by monocytic cells undergoing apoptosis J. Leukoc. Biol., June 1, 2008; 83(6): 1379 - 1381. [Abstract] [Full Text] [PDF]

				N. Shtraizent, E. Eliyahu, J.-H. Park, X. He, R. Shalgi, and E. H. Schuchman Autoproteolytic Cleavage and Activation of Human Acid Ceramidase J. Biol. Chem., April 25, 2008; 283(17): 11253 - 11259. [Abstract] [Full Text] [PDF]

				M. Canault, A. S. Leroyer, F. Peiretti, G. Leseche, A. Tedgui, B. Bonardo, M.-C. Alessi, C. M. Boulanger, and G. Nalbone Microparticles of Human Atherosclerotic Plaques Enhance the Shedding of the Tumor Necrosis Factor-{alpha} Converting Enzyme/ADAM17 Substrates, Tumor Necrosis Factor and Tumor Necrosis Factor Receptor-1 Am. J. Pathol., November 1, 2007; 171(5): 1713 - 1723. [Abstract] [Full Text] [PDF]

				H. Ait-Oufella, K. Kinugawa, J. Zoll, T. Simon, J. Boddaert, S. Heeneman, O. Blanc-Brude, V. Barateau, S. Potteaux, R. Merval, et al. Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice Circulation, April 24, 2007; 115(16): 2168 - 2177. [Abstract] [Full Text] [PDF]

				O. P. Blanc-Brude, E. Teissier, Y. Castier, G. Leseche, A.-P. Bijnens, M. Daemen, B. Staels, Z. Mallat, and A. Tedgui IAP Survivin Regulates Atherosclerotic Macrophage Survival Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 901 - 907. [Abstract] [Full Text] [PDF]

				M.-L. Liu, M. P. Reilly, P. Casasanto, S. E. McKenzie, and K. J. Williams Cholesterol Enrichment of Human Monocyte/Macrophages Induces Surface Exposure of Phosphatidylserine and the Release of Biologically-Active Tissue Factor-Positive Microvesicles Arterioscler Thromb Vasc Biol, February 1, 2007; 27(2): 430 - 435. [Abstract] [Full Text] [PDF]

				T. Minamino and I. Komuro Vascular Cell Senescence: Contribution to Atherosclerosis Circ. Res., January 5, 2007; 100(1): 15 - 26. [Abstract] [Full Text] [PDF]

				S. Camino-Lopez, V. Llorente-Cortes, J. Sendra, and L. Badimon Tissue factor induction by aggregated LDL depends on LDL receptor-related protein expression (LRP1) and Rho A translocation in human vascular smooth muscle cells Cardiovasc Res, January 1, 2007; 73(1): 208 - 216. [Abstract] [Full Text] [PDF]

				C. Mineo, H. Deguchi, J. H. Griffin, and P. W. Shaul Endothelial and Antithrombotic Actions of HDL Circ. Res., June 9, 2006; 98(11): 1352 - 1364. [Abstract] [Full Text] [PDF]

				A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]

				E. Gulbins and P. L. Li Physiological and pathophysiological aspects of ceramide Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R11 - R26. [Abstract] [Full Text] [PDF]

				V. Fuster, P. R. Moreno, Z. A. Fayad, R. Corti, and J. J. Badimon Atherothrombosis and High-Risk Plaque: Part I: Evolving Concepts J. Am. Coll. Cardiol., September 20, 2005; 46(6): 937 - 954. [Abstract] [Full Text] [PDF]

				A. Shimizu, K. Yamada, S. Yamamoto, J. M. Lavelle, R. N. Barth, S. C. Robson, D. H. Sachs, and R. B. Colvin Thrombotic Microangiopathic Glomerulopathy in Human Decay Accelerating Factor-Transgenic Swine-to-Baboon Kidney Xenografts J. Am. Soc. Nephrol., September 1, 2005; 16(9): 2732 - 2745. [Abstract] [Full Text] [PDF]

				C. M. Boulanger and A. Tedgui Dying for attention: Microparticles and angiogenesis Cardiovasc Res, July 1, 2005; 67(1): 1 - 3. [Full Text] [PDF]

				M. Benagiano, M. M. D'Elios, A. Amedei, A. Azzurri, R. van der Zee, A. Ciervo, G. Rombola, S. Romagnani, A. Cassone, and G. Del Prete Human 60-kDa Heat Shock Protein Is a Target Autoantigen of T Cells Derived from Atherosclerotic Plaques J. Immunol., May 15, 2005; 174(10): 6509 - 6517. [Abstract] [Full Text] [PDF]

				M. P.J. de Winther, E. Kanters, G. Kraal, and M. H. Hofker Nuclear Factor {kappa}B Signaling in Atherogenesis Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 904 - 914. [Abstract] [Full Text] [PDF]

				T. Nakazawa, T. Chiba, E. Kaneko, K. Yui, M. Yoshida, and K. Shimokado Insulin Signaling in Arteries Prevents Smooth Muscle Apoptosis Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 760 - 765. [Abstract] [Full Text] [PDF]

				S. A. Summers and D. H. Nelson A Role for Sphingolipids in Producing the Common Features of Type 2 Diabetes, Metabolic Syndrome X, and Cushing's Syndrome Diabetes, March 1, 2005; 54(3): 591 - 602. [Abstract] [Full Text] [PDF]

				P. R. Moreno and V. Fuster New aspects in the pathogenesis of diabetic atherothrombosis J. Am. Coll. Cardiol., December 21, 2004; 44(12): 2293 - 2300. [Abstract] [Full Text] [PDF]

				Q. Cai, L. Lanting, and R. Natarajan Interaction of Monocytes With Vascular Smooth Muscle Cells Regulates Monocyte Survival and Differentiation Through Distinct Pathways Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2263 - 2270. [Abstract] [Full Text] [PDF]

				M. L. Rossi, N. Marziliano, P. A. Merlini, E. Bramucci, U. Canosi, G. Belli, D. Z. Parenti, P. M. Mannucci, and D. Ardissino Different Quantitative Apoptotic Traits in Coronary Atherosclerotic Plaques From Patients With Stable Angina Pectoris and Acute Coronary Syndromes Circulation, September 28, 2004; 110(13): 1767 - 1773. [Abstract] [Full Text] [PDF]

				R. Bhatia, K. Matsushita, M. Yamakuchi, C. N. Morrell, W. Cao, and C. J. Lowenstein Ceramide Triggers Weibel-Palade Body Exocytosis Circ. Res., August 6, 2004; 95(3): 319 - 324. [Abstract] [Full Text] [PDF]

				K. A. Lindstedt, M. J. Leskinen, and P. T. Kovanen Proteolysis of the Pericellular Matrix: A Novel Element Determining Cell Survival and Death in the Pathogenesis of Plaque Erosion and Rupture Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1350 - 1358. [Abstract] [Full Text] [PDF]

				V. Llorente-Cortes, M. Otero-Vinas, S. Camino-Lopez, O. Llampayas, and L. Badimon Aggregated Low-Density Lipoprotein Uptake Induces Membrane Tissue Factor Procoagulant Activity and Microparticle Release in Human Vascular Smooth Muscle Cells Circulation, July 27, 2004; 110(4): 452 - 459. [Abstract] [Full Text] [PDF]

				J. F Viles-Gonzalez, V. Fuster, and J. J Badimon Atherothrombosis: A widespread disease with unpredictable and life-threatening consequences Eur. Heart J., July 2, 2004; 25(14): 1197 - 1207. [Abstract] [Full Text] [PDF]

				S. Sugiyama, K. Kugiyama, M. Aikawa, S. Nakamura, H. Ogawa, and P. Libby Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression: Involvement of Myeloperoxidase-Mediated Oxidant in Plaque Erosion and Thrombogenesis Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1309 - 1314. [Abstract] [Full Text] [PDF]

				S. Rajagopalan, E. C. Somers, R. D. Brook, C. Kehrer, D. Pfenninger, E. Lewis, A. Chakrabarti, B. C. Richardson, E. Shelden, W. J. McCune, et al. Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity Blood, May 15, 2004; 103(10): 3677 - 3683. [Abstract] [Full Text] [PDF]

				M. J. VanWijk, E. VanBavel, A. Sturk, and R. Nieuwland Microparticles in cardiovascular diseases Cardiovasc Res, August 1, 2003; 59(2): 277 - 287. [Abstract] [Full Text] [PDF]

				M. Benagiano, A. Azzurri, A. Ciervo, A. Amedei, C. Tamburini, M. Ferrari, J. L. Telford, C. T. Baldari, S. Romagnani, A. Cassone, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions PNAS, May 27, 2003; 100(11): 6658 - 6663. [Abstract] [Full Text] [PDF]

				W. Martinet, M. W.M. Knaapen, G. R.Y. De Meyer, A. G. Herman, and M. M. Kockx Overexpression of the Anti-Apoptotic Caspase-2 Short Isoform in Macrophage-Derived Foam Cells of Human Atherosclerotic Plaques Am. J. Pathol., March 1, 2003; 162(3): 731 - 736. [Abstract] [Full Text] [PDF]

				R. Corti, V. Fuster, and J. J. Badimon Pathogenetic concepts of acute coronary syndromes J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 7S - 14S. [Abstract] [Full Text] [PDF]

				P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]

				G. Valen The basic biology of apoptosis and its implications for cardiac function and viability Ann. Thorac. Surg., February 1, 2003; 75(2): S656 - 660. [Abstract] [Full Text] [PDF]

				F. J. Schoen and R. F. Padera Jr. Cardiac Surgical Pathology Card. Surg. Adult, January 1, 2003; 2(2003): 119 - 185. [Full Text]

				N. Werner and G. Nickenig AT1 receptors in atherosclerosis: biological effects including growth, angiogenesis, and apoptosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A9 - A13. [Abstract] [PDF]

				W. Martinet, D. M. Schrijvers, G. R.Y. De Meyer, J. Thielemans, M. W.M. Knaapen, A. G. Herman, and M. M. Kockx Gene Expression Profiling of Apoptosis-Related Genes in Human Atherosclerosis: Upregulation of Death-Associated Protein Kinase Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2023 - 2029. [Abstract] [Full Text] [PDF]

				R. S. Barua, J. A. Ambrose, D. C. Saha, and L.-J. Eales-Reynolds Smoking Is Associated With Altered Endothelial-Derived Fibrinolytic and Antithrombotic Factors: An In Vitro Demonstration Circulation, August 20, 2002; 106(8): 905 - 908. [Abstract] [Full Text] [PDF]

				J. Huber, A. Vales, G. Mitulovic, M. Blumer, R. Schmid, J. L. Witztum, B. R. Binder, and N. Leitinger Oxidized Membrane Vesicles and Blebs From Apoptotic Cells Contain Biologically Active Oxidized Phospholipids That Induce Monocyte-Endothelial Interactions Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 101 - 107. [Abstract] [Full Text] [PDF]

				T. Levade, N. Auge, R. J. Veldman, O. Cuvillier, A. Negre-Salvayre, and R. Salvayre Sphingolipid Mediators in Cardiovascular Cell Biology and Pathology Circ. Res., November 23, 2001; 89(11): 957 - 968. [Abstract] [Full Text] [PDF]

				J.-B. Michel Contrasting Outcomes of Atheroma Evolution: Intimal Accumulation Versus Medial Destruction Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1389 - 1392. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mallat, Z. Articles by Tedgui, A. Search for Related Content PubMed PubMed Citation Articles by Mallat, Z. Articles by Tedgui, A. Related Collections Apoptosis Pathophysiology Acute coronary syndromes