Published online before print December 13, 2007, doi: 10.1161/ATVBAHA.107.151340
© 2008 American Heart Association, Inc.
Cell Biology/Signaling |
Activated Mast Cells Induce Endothelial Cell Apoptosis by a Combined Action of Chymase and Tumor Necrosis Factor-
From the Wihuri Research Institute, Helsinki, Finland.
Correspondence to Ken A. Lindstedt, Wihuri Research Institute, Kalliolinnantie 4, 00140 Helsinki, Finland. E-mail ken.lindstedt{at}wri.fi
Abstract
Objective— Activated mast cells (MCs) induce endothelial cell (EC) apoptosis in vitro and are present at sites of plaque erosions in vivo. To further elucidate the role of MCs in endothelial apoptosis and consequently in plaque erosion, we have studied the molecular mechanisms involved in MC-induced EC apoptosis.
Methods and Results— Primary cultures of rat cardiac microvascular ECs (RCMECs) and human coronary artery ECs (HCAECs) were treated either with rat MC releasate (ie, mediators released on MC activation), rat chymase and tumor necrosis factor-
(TNF-), or with human chymase and TNF-, respectively. MC releasate induced RCMEC apoptosis by inactivating the focal adhesion kinase (FAK) and Akt-dependent survival signaling pathway, and apoptosis was partially inhibited by chymase and TNF- inhibitors. Chymase avidly degraded both vitronectin (VN) and fibronectin (FN) produced by the cultured RCMECs. In addition, MC releasate inhibited the activation of NF-
B (p65) and activated caspase-8 and -9. Moreover, in HCAECs, human chymase and TNF- induced additive levels of apoptosis.
Conclusions— Activated MCs induce EC apoptosis by multiple mechanisms: chymase inactivates the FAK-mediated cell survival signaling, and TNF- triggers apoptosis. Thus, by inducing EC apoptosis, MCs may contribute to plaque erosion and complications of atherosclerosis.
Activated mast cells are present in the subendothelial space of coronary atheromas, colocalize with plaque erosions and parietal microthrombi, and induce endothelial cell apoptosis in vitro by a combined action of chymase and TNF-. Thus, activated mast cells may contribute to plaque erosion with the progression of atherosclerosis and its complications.
Key Words: atherosclerosis • mast cell • apoptosis • chymase • plaque erosion
The most important pathological processes underlying the sudden onset of acute coronary syndromes, including unstable angina and acute myocardial infarction, are focal erosions and ruptures of a vulnerable coronary plaque.1 Although erosions of coronary plaques account for as much as 30% of the fatal acute myocardial infarctions and sudden coronary deaths,2 the molecular mechanisms of plaque erosion have remained enigmatic. One possible cause of plaque erosion is apoptosis of the involved endothelial cells (ECs).3 Indeed, patients with unstable angina or myocardial infarction have increased levels of circulating EC-derived apoptotic microparticles,4 and patients with symptomatic internal carotid artery plaques have increased numbers of apoptotic ECs.5 EC apoptosis is especially seen in downstream areas of atherosclerotic plaques subjected to aberrant hemodynamic forces including turbulent blood flow.6
The vulnerable sites of atherosclerotic plaques also contain an increased number of mast cells (MCs) that show signs of activation by degranulation, which is a prerequisite for the release of preformed mediators, both insoluble and soluble.7,8 We have previously shown that activated rat serosal MCs induce apoptosis of rat cardiac microvascular ECs (RCMECs) in vitro, by a mechanism that involves the presence of both insoluble tumor necrosis factor- (TNF-) in the granule-remnant fraction and soluble TNF- in the granule-remnant free supernatant.9 However, TNF- alone could not explain the observed effects,9 suggesting that other components of the MC releasate may have been involved. Chymase, the neutral serine protease of MCs, has been shown to induce apoptosis of smooth muscle cells (SMCs),10 myocytes,11 and epithelial cells.12 Recently, we have shown that the MC-derived proteases, chymase and tryptase, when incubated with arterial segments induce plaque erosion ex vivo.13 Furthermore, we have also shown that activated MCs are present at sites of such erosions,8,13 and that the number of MCs at plaque erosions correlates with the number of parietal microthrombi.13 Moreover, targeted activation of perivascular MCs in advanced plaques of apolipoprotein E–deficient mice sharply increases the incidence of intraplaque hemorrhage and vascular leakage, suggesting MC-mediated EC damage.14
In normal arteries, EC survival and function largely depend on the existing hemodynamic forces.15 High laminar shear stress protects ECs from ensuing apoptosis16–18 by inducing the expression of antiapoptotic genes19 and integrins.20 The interactions between EC integrins and the extracellular matrix (ECM) components of the arterial wall are especially critical for the proper function of the endothelium, because ECs lacking this interaction rapidly undergo apoptosis.21–23 The most important integrins for EC survival are vβ3 and 5β1 integrins, known as the primary receptors for the ECM components vitronectin (VN) and fibronectin (FN), respectively.24,25 Because integrins induce their cellular effects via focal adhesions, ie, complex ECM adhesion sites in the plasma membrane, the integrity of the focal adhesions is important for EC survival. Focal adhesion kinase (FAK) is a central molecule of focal adhesions26 and its activation, ie, phosphorylation, is induced by binding of integrins to VN27 and FN.28,29 Activation of FAK leads to downstream activation of other signaling proteins such as Akt and nuclear factor B (NF-B).30,31
In the present study, we show that activated MCs induce EC apoptosis through a novel dual mechanism involving parallel and additive effects of chymase and TNF-. By avidly degrading the pericellular matrix components VN and FN, and by inactivating the focal adhesion-mediated EC survival-signaling pathways, chymase renders the otherwise resistant ECs susceptible to apoptosis. Subsequently, TNF- released together with chymase triggers apoptosis in the protease-sensitized ECs.
Methods
Please see the online supplemental data section at http://atvb. ahajournals.org for a detailed Methods section.
Culture of RCMECs and Human Coronary Artery ECs
RCMECs were isolated from male Wistar rat (300 to 500 g) myocardium as described in the detailed Methods section online, and cultured in M199 culture media (Cat. M7528, Sigma) supplemented with 15% FBS, 2 mmol/L L-glutamine, 250 U/mL PS and 2.5 µg/mL amphotericin B. Experiments were performed with ECs of 2nd to 6th passages in serum-free conditions.
Human coronary artery ECs (HCAECs; PromoCell, Heidelberg, Germany) were cultured in Endothelial Cell Growth Medium MV (PromoCell) supplemented with 5% fetal calf serum (PromoCell), growth factors (0.4% endothelial cell growth supplement/heparin, 10 ng/mL epidermal growth factor, 1 µg/mL hydrocortison; PromoCell), and antibiotics (100 U/mL PS, 50 ng/mL amphotericin B; Cambrex) according to instructions of the supplier. Experiments were performed with cells of 7th passage in serum-free conditions.
Statistical Analysis
Data, shown as means±SDs, were analyzed by the Student t test for determination of the significance of differences, which were considered to be statistically significant at a probability value of less than 0.05.
Results
To further elucidate the mechanisms involved in MC-mediated EC apoptosis,9 RCMECs were treated with rat MC releasate, in the absence or presence of a neutralizing TNF- antibody and a chymase inhibitor (TRINH). The commercial agent (compound 48/80) used here to induce MC degranulation did not affect the observed effects in the treated RCMECs (Figure 1). The MC releasate induced a 4-fold increase in the level of apoptotic cells (2.7%±0.84 versus 0.7%±0.22), which was partially inhibited in the presence of a neutralizing TNF- antibody (1.7%±0.34) or a chymase inhibitor (TRINH; 1.0%±0.44; Figure 1). When both inhibitors were added together, the level of apoptosis was similar to the level seen in control cells (0.9%±0.38 versus 0.7%±0.22 in control; Figure 1). However, the difference in the level of inhibition of apoptosis between the individual and combined treatments was significant (P<0.01) only between the neutralizing TNF- antibody (1.7%±0.34) and the combination of a neutralizing TNF- antibody and the chymase inhibitor, TRINH (0.9%±0.38). These results suggest that the MC releasate contains multiple components, notably chymase and TNF-, that are capable of inducing EC apoptosis.
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To study the effect of MC releasate on the levels and activities of FAK and Akt, two central players in the cell-survival signaling pathways,31 RCMECs were treated with MC releasate. As shown in Figure 2, MC releasate efficiently induced both dephosphorylation and degradation of FAK (Figure 2A and 2B), whereas the releasate had a minor effect on the phosphorylation of Akt compared with the compound 48/80 control (Figure 2C), and no effect on the Akt protein level (Figure 2D). To determine which of the two apoptosis-inducing components in the mast cell releasate, ie, chymase or TNF-, are involved in the observed effect on cell-survival signaling, RCMECs were treated with purified rat chymase and recombinant rat TNF-. Chymase alone induced both dephosphorylation and degradation of FAK (Figure 3A and 3B), whereas Akt was dephosphorylated but not significantly degraded (Figure 3C and 3D). Whereas equivalent amounts of purified chymase induced a similar degree of FAK dephosphorylation and degradation as the MC releasate (Figure 2A and 2B), TNF- did not have a significant effect on phosphorylation or degradation of either FAK or Akt.
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Because chymase induces apoptosis of SMCs32 and epithelial cells12 by degrading fibronectin (FN), and because also vitronectin (VN) is necessary for focal adhesions and cell survival signaling,30,33 we next studied the effect of MC chymase on purified VN and FN, as well as on VN and FN produced by the RCMECs. As shown in Figure 4, chymase avidly degraded purified VN (Figure 4A) and FN (Figure 4B). In addition, incubation of cultured RCMECs with chymase induced a significant degradation of VN and FN present in their extra- and pericellular matrix (Figure 4C and 4D).
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As the cellular effects of vβ3 integrin-mediated outside-in survival signaling in ECs is controlled by NF-B,30 a transcription factor also known to regulate the delicate balance of pro–inflammatory and anti–inflammatory genes in the atherosclerotic process,34 we studied the effect of MC releasate on NF-B. Here we show, by means of immunostaining of the p65 subunit of NF-B and by EMSA, that MC releasate induces inhibition of the nuclear translocation of NF-B (see supplemental Figure I). In control cells, p65 was present both in the nucleus and in the cytoplasm of RCMECs (supplemental Figure IA, top left), whereas when treated with MC releasate the nuclear staining was lost (supplemental Figure IA, top right). Furthermore, RCMECs treated with lipopolysaccharide (LPS), an efficient inducer of NF-B activity, showed a strong nuclear staining of p65 (supplemental Figure IA, bottom left), whereas LPS-activated RCMECs treated with MC releasate did not (supplemental Figure IA, bottom right). In addition, by EMSA analysis we could show that the chymase and TNF-–containing granule remnants (GRs) present in the MC releasate, abolished the nuclear translocation of p65 (supplemental Figure IB).
Furthermore, to analyze the onset of apoptotic death in the MC releasate-treated RCMECs, the levels of initiator caspase-8 and -9 were measured with a fluorometric assay. As shown in Figure 5A and 5B, MC releasate induced the activities of both caspase-8 and -9, which were partially inhibited by their specific inhibitors, Z-IETD-FMK and Z-LEHD-FMK, respectively. Furthermore, a combined inhibition of caspase-8 and -9 resulted in an additive reduction in the degree of apoptosis (Figure 5C).
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Finally, to investigate whether chymase and TNF- could induce apoptosis also in human ECs, isolated ECs from human coronary arteries (HCAECs) were treated with recombinant human chymase and TNF-. Indeed, as shown in Figure 6, both chymase and TNF- alone were able to induce apoptosis in HCAECs (33.4±2.13% and 29.9±2.17% as compared with 16.7±1.65% of apoptotic cells in controls), and the level of apoptosis was significantly increased being additive when chymase and TNF- were added together (49.2±2.16% apoptotic cells).
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Discussion
In the present study, we show that activated mast cells (MCs), by a combined action of chymase and TNF-, induce apoptosis in both RCMECs and HCAECs in vitro. The molecular mechanisms of MC-mediated apoptosis involve degradation of VN and FN, with subsequent inactivation of the FAK, Akt, and NF-B signaling pathways, and activation of both caspase-8 and -9.
It is well known that MCs contain a broad variety of mediators, by which they are capable of orchestrating both innate and acquired immune reactions.35 In addition to their extremely potential repertoire of effector molecules, the strategic location of MCs at sites such as skin and vascular and mucosal barriers support an evolutionary role for them in primary host defense, ie, in killing invading parasites and bacteria, as well as infected and damaged cells.35 Because a "clean" process of apoptotic death, in contrast to "dirty" necrotic death, would be the most feasible and physiological mechanism of removing such intruders, one could reason that MCs, as a part of the normal host defense, would possess means to induce proapoptotic mechanisms in vivo. Here we describe a novel cell-mediated proapoptotic mechanism, in which activated MCs use a unique sequence of multiple events to induce apoptosis in ECs in vitro. This sequence of events involves the parallel and additive action of two simultaneously acting effector molecules, chymase and TNF-, secreted by the activated MCs. The proteolytically active chymase degrades the pericellular matrix components VN and FN and inhibits the FAK- and NF-B–mediated antiapoptotic signaling mechanisms, sensitizing the normally apoptosis-resistant ECs to proapoptotic stress. Thus, based on our data it seems evident that the chymase-induced inhibition of both FAK- and Akt-phosphorylation occurs through indirect mechanisms, ie, via degradation of the extracellular matrix components VN and FN that are necessary for the maintenance of focal adhesions, followed by an increased degradation of the downstream molecules involved in focal adhesion signaling by intracellular proteases.
The observed MC-induced activation of both caspase-8 and -9, the initiator caspases of the extrinsic and intrinsic pathways of apoptosis, respectively, also suggests an interaction between the two death pathways. Thus, chymase may trigger the intrinsic pathway of apoptosis with the concomitant activation of caspase-9. Subsequently, in the absence of integrin-maintained antiapoptotic pathways, TNF- may induce EC apoptosis via the extrinsic pathway, ie, by activation of caspase-8. Interestingly, the ability of TNF- to induce apoptosis in ECs is significantly increased when protein or RNA synthesis is inhibited.36,37 Thus, by simultaneously suppressing antiapoptotic and inducing apoptotic mechanisms, MCs may actively disturb the balance between cell survival and death in neighboring ECs.
In our experiments, the chymase-mediated effect on RCMEC apoptosis seems to rely on its ability to proteolytically degrade ECM proteins VN and FN. It has been shown that FN antiadhesive fragment is buried in intact FN,38 but on generation by matrix metalloproteinase (MMP) 2 becomes exposed.39 In addition, specific FN fragments have been shown to induce apoptosis of SMCs,32 epithelial cells,40 ECs41 and periodontal ligament cells.42 However, some FN fragments have been shown to rather promote human retinal EC adhesion and proliferation43 indicating that the FN fragments have different effects depending on how they are generated. Also, blocking peptides of vβ3 integrins have been shown to induce apoptosis in ECs,44–46 indicating that also VN is an important mediator of cell survival. Moreover, RGD-containing peptides can also enter cells through endocytic pathways and thereby induce apoptosis by direct activation of caspase-3.47,48 In addition, it has been shown that unligated integrins can induce apoptosis of adherent cells49 by a mechanism involving the direct activation of caspase-8. However, our present results show that the major effect of MC-induced RCMEC apoptosis is attributable to the proteolytic degradation of the matrix components, VN and FN, which intactness is necessary for the maintenance of focal adhesions and cell survival. The chymase-generated VN and FN peptide fragments have only a minor direct effect on RCMEC apoptosis (data not shown).
Under physiological conditions, the mechanism of MC activation, which is a prerequisite for the release of its powerful mediators, is strictly regulated.50 However, under pathological conditions, such as atherogenesis, the regulation of MC activation may become uncontrolled, leading to undesired and excessive tissue destruction. Thus, the role of activated MCs in the process of plaque erosion and rupture may result from a vicious circle, in which an ongoing ancient remodeling process is aiming at repair, but rather initiates an uncontrolled process of pathological destruction. Thus, by secreting chymase and TNF-, activated MCs induce apoptosis of ECs in vitro by a mechanism involving degradation of VN and FN with subsequent inactivation of FAK, Akt, and NF-B and activation of caspase-8 and -9. In excess, this cellular derangement may contribute to focal erosion of atherosclerotic plaques with its clinical sequelae.
Acknowledgments
We are grateful to Leena Saikko (Department of Pathology, University of Helsinki) and Monica Schoultz (Transplantation Laboratory, University of Helsinki) for skillfully performing the flow cytometric analysis. We also gratefully acknowledge Jaana Tuomikangas, Mari Jokinen, Elina Kaperi, and Maija Atuegwu for excellent technical assistance.
Sources of Funding
The Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation.
Disclosures
None.
Footnotes
Original received July 6, 2007; final version accepted November 29, 2007.
References
1. Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol. 2005; 46: 937–954.
2. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W, Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003; 108: 1664–1672.
3. Durand E, Scoazec A, Lafont A, Boddaert J, Al Hajzen A, Addad F, Mirshahi M, Desnos M, Tedgui A, Mallat Z. In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation: a clue to the understanding of the mechanisms of thrombotic plaque erosion. Circulation. 2004; 109: 2503–2506.
4. 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.
5. Trostdorf F, Landgraf C, Kablau M, Schmitz-Rixen T, Sitzer M. Increased endothelial cell apoptosis in symptomatic high-grade carotid artery stenosis: preliminary data. Eur J Vasc Endovasc Surg. 2007; 33: 65–68.[CrossRef][Medline] [Order article via Infotrieve]
6. Tricot O, Mallat Z, Heymes C, Belmin J, Leseche G, Tedgui A. Relation between endothelial cell apoptosis and blood flow direction in human atherosclerotic plaques. Circulation. 2000; 101: 2450–2453.
7. Kaartinen M, Penttilä A, Kovanen PT. Accumulation of activated mast cells in the shoulder region of human coronary atheroma, the predilection site of atheromatous rupture. Circulation. 1994; 90: 1669–1678.
8. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation. 1995; 92: 1084–1088.
9. Lätti S, Leskinen M, Shiota N, Wang Y, Kovanen PT, Lindstedt KA. Mast cell-mediated apoptosis of endothelial cells in vitro: a paracrine mechanism involving TNF-alpha-mediated down-regulation of bcl-2 expression. J Cell Physiol. 2003; 195: 130–138.[CrossRef][Medline] [Order article via Infotrieve]
10. Leskinen M, Wang Y, Leszczynski D, Lindstedt KA, Kovanen PT. Mast cell chymase induces apoptosis of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001; 21: 516–522.
11. Hara M, Matsumori A, Ono K, Kido H, Hwang MW, Miyamoto T, Iwasaki A, Okada M, Nakatani K, Sasayama S. Mast cells cause apoptosis of cardiomyocytes and proliferation of other intramyocardial cells in vitro. Circulation. 1999; 100: 1443–1449.
12. Ebihara N, Takai S, Miyazaki M, Murakami A. Mast cell chymase induces conjunctival epithelial cell apoptosis by a mechanism involving degradation of fibronectin. Curr Eye Res. 2005; 30: 429–435.[CrossRef][Medline] [Order article via Infotrieve]
13. Mäyränpää MI, Heikkilä HM, Lindstedt KA, Walls AF, Kovanen PT. Desquamation of human coronary artery endothelium by human mast cell proteases: implications for plaque erosion. Coron Artery Dis. 2006; 17: 611–621.[CrossRef][Medline] [Order article via Infotrieve]
14. Bot I, de Jager SC, Zernecke A, Lindstedt KA, van Berkel TJ, Weber C, Biessen EA. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. Circulation. 2007; 115: 2516–2525.
15. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995; 92: 657–671.
16. Dimmeler S, Haendeler J, Rippmann V, Nehls M, Zeiher AM. Shear stress inhibits apoptosis of human endothelial cells. FEBS Lett. 1996; 399: 71–74.[CrossRef][Medline] [Order article via Infotrieve]
17. Kaiser D, Freyberg MA, Friedl P. Lack of hemodynamic forces triggers apoptosis in vascular endothelial cells. Biochem Biophys Res Commun. 1997; 231: 586–590.[CrossRef][Medline] [Order article via Infotrieve]
18. Cho A, Mitchell L, Koopmans D, Langille BL. Effects of changes in blood flow rate on cell death and cell proliferation in carotid arteries of immature rabbits. Circ Res. 1997; 81: 328–337.
19. Bartling B, Tostlebe H, Darmer D, Holtz J, Silber RE, Morawietz H. Shear stress-dependent expression of apoptosis-regulating genes in endothelial cells. Biochem Biophys Res Commun. 2000; 278: 740–746.[CrossRef][Medline] [Order article via Infotrieve]
20. Urbich C, Walter DH, Zeiher AM, Dimmeler S. Laminar shear stress upregulates integrin expression: role in endothelial cell adhesion and apoptosis. Circ Res. 2000; 87: 683–689.
21. Meredith JE Jr, Fazeli B, Schwartz MA. The extracellular matrix as a cell survival factor. Mol Biol Cell. 1993; 4: 953–961.[Abstract]
22. Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 1994; 124: 619–626.
23. Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol. 1997; 9: 701–706.[CrossRef][Medline] [Order article via Infotrieve]
24. Wary KK, Mainiero F, Isakoff SJ, Marcantonio EE, Giancotti FG. The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell. 1996; 87: 733–743.[CrossRef][Medline] [Order article via Infotrieve]
25. Dejana E, Colella S, Conforti G, Abbadini M, Gaboli M, Marchisio PC. Fibronectin and vitronectin regulate the organization of their respective Arg-Gly-Asp adhesion receptors in cultured human endothelial cells. J Cell Biol. 1988; 107: 1215–1223.
26. Romer LH, Birukov KG, Garcia JG. Focal adhesions: paradigm for a signaling nexus. Circ Res. 2006; 98: 606–616.
27. Burridge K, Turner CE, Romer LH. Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. J Cell Biol. 1992; 119: 893–903.
28. Guan JL, Trevithick JE, Hynes RO. Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120-kDa protein. Cell Regul. 1991; 2: 951–964.[Medline] [Order article via Infotrieve]
29. Guan JL, Shalloway D. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature. 1992; 358: 690–692.[CrossRef][Medline] [Order article via Infotrieve]
30. Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM. NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. J Cell Biol. 1998; 141: 1083–1093.
31. Stupack DG, Cheresh DA. Get a ligand, get a life: integrins, signaling and cell survival. J Cell Sci. 2002; 115: 3729–3738.
32. Leskinen MJ, Lindstedt KA, Wang Y, Kovanen PT. Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions. Arterioscler Thromb Vasc Biol. 2003; 23: 238–243.
33. Isik FF, Gibran NS, Jang YC, Sandell L, Schwartz SM. Vitronectin decreases microvascular endothelial cell apoptosis. J Cell Physiol. 1998; 175: 149–155.[CrossRef][Medline] [Order article via Infotrieve]
34. de Winther MP, Kanters E, Kraal G, Hofker MH. Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol. 2005; 25: 904–914.
35. Kinet JP. The essential role of mast cells in orchestrating inflammation. Immunol Rev. 2007; 217: 5–7.[CrossRef][Medline] [Order article via Infotrieve]
36. Pohlman TH, Harlan JM. Human endothelial cell response to lipopolysaccharide, interleukin-1, and tumor necrosis factor is regulated by protein synthesis. Cell Immunol. 1989; 119: 41–52.[CrossRef][Medline] [Order article via Infotrieve]
37. Polunovsky VA, Wendt CH, Ingbar DH, Peterson MS, Bitterman PB. Induction of endothelial cell apoptosis by TNF alpha: modulation by inhibitors of protein synthesis. Exp Cell Res. 1994; 214: 584–594.[CrossRef][Medline] [Order article via Infotrieve]
38. Fukai F, Hasebe S, Ueki M, Mutoh M, Ohgi C, Takahashi H, Takeda K, Katayama T. Identification of the anti-adhesive site buried within the heparin-binding domain of fibronectin. J Biochem (Tokyo). 1997; 121: 189–192.[Medline] [Order article via Infotrieve]
39. Watanabe K, Takahashi H, Habu Y, Kamiya-Kubushiro N, Kamiya S, Nakamura H, Yajima H, Ishii T, Katayama T, Miyazaki K, Fukai F. Interaction with heparin and matrix metalloproteinase 2 cleavage expose a cryptic anti-adhesive site of fibronectin. Biochemistry. 2000; 39: 7138–7144.[CrossRef][Medline] [Order article via Infotrieve]
40. Schedin P, Strange R, Mitrenga T, Wolfe P, Kaeck M. Fibronectin fragments induce MMP activity in mouse mammary epithelial cells: evidence for a role in mammary tissue remodeling. J Cell Sci. 2000; 113 (Pt 5): 795–806.[Abstract]
41. Fukai F, Mashimo M, Akiyama K, Goto T, Tanuma S, Katayama T. Modulation of apoptotic cell death by extracellular matrix proteins and a fibronectin-derived antiadhesive peptide. Exp Cell Res. 1998; 242: 92–99.[CrossRef][Medline] [Order article via Infotrieve]
42. Dai R, Iwama A, Wang S, Kapila YL. Disease-associated fibronectin matrix fragments trigger anoikis of human primary ligament cells: p53 and c-myc are suppressed. Apoptosis. 2005; 10: 503–512.[CrossRef][Medline] [Order article via Infotrieve]
43. Wilson SH, Ljubimov AV, Morla AO, Caballero S, Shaw LC, Spoerri PE, Tarnuzzer RW, Grant MB. Fibronectin fragments promote human retinal endothelial cell adhesion and proliferation and ERK activation through alpha5beta1 integrin and PI 3-kinase. Invest Ophthalmol Vis Sci. 2003; 44: 1704–1715.
44. Meerovitch K, Bergeron F, Leblond L, Grouix B, Poirier C, Bubenik M, Chan L, Gourdeau H, Bowlin T, Attardo G. A novel RGD antagonist that targets both alphavbeta3 and alpha5beta1 induces apoptosis of angiogenic endothelial cells on type I collagen. Vascul Pharmacol. 2003; 40: 77–89.[CrossRef][Medline] [Order article via Infotrieve]
45. Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994; 79: 1157–1164.[CrossRef][Medline] [Order article via Infotrieve]
46. Erdreich-Epstein A, Tran LB, Cox ÓT, Huang EY, Laug WE, Shimada H, Millard M. Endothelial apoptosis induced by inhibition of integrins alphavbeta3 and alphavbeta5 involves ceramide metabolic pathways. Blood. 2005; 105: 4353–4361.
47. Buckley CD, Pilling D, Henriquez NV, Parsonage G, Threlfall K, Scheel-Toellner D, Simmons DL, Akbar AN, Lord JM, Salmon M. RGD peptides induce apoptosis by direct caspase-3 activation. Nature. 1999; 397: 534–539.[CrossRef][Medline] [Order article via Infotrieve]
48. Castel S, Pagan R, Mitjans F, Piulats J, Goodman S, Jonczyk A, Huber F, Vilaró S, Reina M. RGD peptides and monoclonal antibodies, antagonists of alpha(v)-integrin, enter the cells by independent endocytic pathways. Lab Invest. 2001; 81: 1615–1626.[Medline] [Order article via Infotrieve]
49. Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM, Cheresh DA. Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol. 2001; 155: 459–470.
50. Dawicki W, Marshall JS. New and emerging roles for mast cells in host defence. Curr Opin Immunol. 2007; 19: 31–38.[CrossRef][Medline] [Order article via Infotrieve]
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