Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:297-299

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schmidt, A. M.
Right arrow Articles by Stern, D. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schmidt, A. M.
Right arrow Articles by Stern, D. M.
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:297.)
© 2001 American Heart Association, Inc.

Editorial

Chemokines on the Rise

MCP-1 and Restenosis

Ann Marie Schmidt; David M. Stern

From the Departments of Surgery, Medicine, and Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY.

Correspondence to Dr David Stern, Department of Surgery, P&S 17-401, College of Physicians and Surgeons of Columbia University, 630 W 168th St, New York, NY 10032. E-mail dms9{at}columbia.edu

Mechanisms underlying restenosis after percutaneous transluminal coronary angioplasty (PTCA) are important to elucidate, as evidenced by the recent success of monoclonal antibodies to platelet glycoprotein IIb/IIIa in preventing restenosis.1 2 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, a report by Cipollone et al3 describes the association of monocyte chemoattractant protein-1 (JE/MCP-1) with restenosis after coronary angioplasty. As discussed below, in view of the biological properties of JE/MCP-1, increased blood levels of this chemokine are likely to represent far more than a simple marker of local vascular disease; rather, we speculate that enhanced expression of JE/MCP-1 provides a window into the pathogenesis of vascular smooth muscle cell (SMC) and mononuclear phagocyte (MP) activation, which underlies restenosis.

Chemokines are a large group of low-molecular-weight polypeptides (8 to 16 kDa) originally recognized for their ability to mediate migration of leukocyte populations toward foci of immune/inflammatory stimuli.4 5 This includes facilitation of leukocyte-endothelial interaction and cell migration itself.6 JE/MCP-1, the prototypical C-C chemokine, is associated with chronic vascular disorders, such as atherosclerosis,7 8 9 10 11 12 unstable angina,13 and congestive heart failure,14 as well as inflammatory states.4 5 15 16 17 18 19 This chemokine exerts its effects on MPs, T-cell helper cells/memory T cells,20 21 natural killer cells,22 23 and basophils, in large part via the receptor CCR2, although other receptors capable of interacting with JE/MCP-1 have been identified.4 5 24 The most potent chemotactic activity of this chemokine appears to be toward MPs. Activation of MPs mediated by JE/MCP-1 involves at least 2 phases: a short-term phase, including elevation of cytosolic calcium, actin polymerization, and upregulation of ß2-integrins, thus allowing cell migration and tight binding to endothelial counterreceptors,4 25 and a longer-term phase, involving expression of the procoagulant initiator tissue factor26 27 and intercellular adhesion molecule-1 (the latter 2 occur in SMCs and MPs) (and other inflammation-associated genes), as well as generation of reactive oxygen intermediates.25 28 29 Taken together, these events form an important shift in cellular properties toward an activated state, and their relevance to host response mechanisms is emphasized by the association of JE/MCP-1 expression with recruitment of MPs into tissues. The latter conclusion is supported by results of studies in transgenic models with targeted expression of JE/MCP-1 expression30 31 32 and experiments in JE/MCP-1–deficient mice,33 as well as correlative work (see Reference 88 ) and studies with blocking antibodies.34

In the context of atherosclerotic vascular disease, there is compelling evidence for a pathogenic role of JE/MCP-1. Expression of JE/MCP-1 has been noted in cell types critical to the formation of such vascular lesions, including endothelium, MPs, and smooth muscle. Experiments with mice rendered genetically deficient in JE/MCP-1 or its key target receptor, CCR2, have shown diminished formation of atherosclerotic lesions.11 35 Bone marrow transplantation with cells from mice overexpressing a JE/MCP-1 transgene into apolipoprotein E–null animals resulted in repopulation of the bone marrow with cells bearing the transgene, along with increased lesion formation, oxidized lipids, and macrophage infiltration.9 The observed elevation of JE/MCP-1 in patients with acute myocardial infarction13 draws this chemokine into the biology of acute events associated with plaque rupture and vascular wall remodelling. These observations are consistent with the results of studies in a canine model of myocardial ischemia/reperfusion, in which JE/MCP-1 expression was noted within an hour of the ischemic insult.36

As a member of the group of "immediate-early" genes whose expression occurs with a rapid time course after exposure to stimuli,37 the brief interval between injury to the vessel wall (ie, angioplasty) and expression of JE/MCP-1 might have been predicted. In a model of balloon injury to normal rabbit aortas, upregulation of JE/MCP-1 transcripts was noted by 1 hour and reached a maximum by 4 hours, returning to baseline by 8 hours.38 In view of the absence of invading MPs during these early times (1 to 4 hours) and the completeness of endothelial denudation, the authors concluded that vascular SMCs were the likely source of JE/MCP-1. These data are consistent with subsequent results in a rat carotid injury model in which early expression of JE/MCP-1 was noted, and administration of neutralizing polyclonal antibody to JE/MCP-1 with different regimens during the first 5 days was associated with diminished neointimal expansion.39 In a porcine iliac artery angioplasty model, early expression of JE/MCP-1 transcripts (by 2 hours) was also observed.40 JE/MCP-1 expression was maximal in the latter model at 8 hours and declined to baseline by 16 to 24 hours. Immunohistochemical analysis of the site of injury performed at 8 hours demonstrated JE/MCP-1 to be predominately associated with MPs. Putting together these observations, it would be predicted that induction of JE/MCP-1 transcripts occurs at the earliest stages after vascular injury in vascular SMCs, and shortly thereafter, in infiltrating MPs.

The observations of Cipollone et al3 suggest an important addition to this view of JE/MCP-1 and the biology of restenosis accompanying angioplasty. In a study of 50 patients undergoing PTCA, the authors observed that patients with restenosis had statistically significant elevations in plasma MCP-1 compared with nonrestenotic patients (mea apolipoprotein E–deficient (apoE–/–) mice. Previous studies sured at 1, 5, 15, and 180 days). In contrast, 2 other chemokines, regulated on activation normally T cell expressed and secreted and interleukin-8, did not follow a similar pattern. There was no difference in baseline levels of JE/MCP-1 in patients who would/would not develop restenosis. Based on multivariate regression analysis, MCP-1 plasma levels at 15 days after angioplasty proved to be a significant independent predictor of restenosis. Two important caveats related to this study, in terms of extrapolation to the larger general population of patients undergoing angioplasty, concern (1) the exclusion of patients who underwent stenting after PTCA from the study and (2) the relatively small number of patients evaluated. However, despite these limitations, this work raises important issues for future study.

In contrast to the previous focus on early expression of JE/MCP-1 after angioplasty in animals with normal vasculature, the data of Cipollone et al3 suggest that in human arteries with underlying atherosclerosis, induction of JE/MCP-1 may be more sustained. There are several mechanisms that could underlie these observations, such as prolonged activation of nuclear factor-{kappa}B and Egr-1 in the injured vessel wall.41 42 43 44 In addition, a role for peroxisome proliferator-activated receptor-{alpha},45 platelet-derived growth factor,38 46 and/or diminished local nitric oxide production47 48 might be involved in the second phase of JE/MCP-1 expression. However, the key point is that one can surmise a positive feedback loop in which mechanisms that would ordinarily limit JE/MCP-1 to a brief pulse (coincident with expression of other chemokines) early after injury of the normal vessel wall have been supplanted by a more sustained stimulus in which JE/MCP-1 expression is potentiated (Fig. 1Down). Such prolonged JE/MCP-1 production could have autocrine/paracrine effects on MPs and SMCs at the site of the lesions and would be reflected in the apparent activation of MPs observed in patients with increased levels of JE/MCP-1.3



View larger version (153K):
[in this window]
[in a new window]
  		Figure 1. Schematic depiction of vascular injury (PTCA) and JE/MCP-1 expression according to an early stage, in which there is a transient burst of JE/MCP-1 production, and a chronic stage, in which there is autocrine/paracrine perpetuation of cell recruitment/activation by JE/MCP-1. EC indicates endothelial cell. The red arrows indicate cells elaborating JE/MCP-1.

Viewed in this context, the observations of Cipollone and colleagues3 provide a potential opportunity to translate results from animal models and clinical observations to therapeutic concepts. At the very least, plasma levels of JE/MCP-1 provide a valuable index of MP activation after angioplasty and are likely to be reflective of events occurring locally in the injured vessel wall. If this extrapolation proves to be valid at the level of pathogenesis of vascular lesions, then interception of the interaction of JE/MCP-1 with its receptor could provide a future therapeutic modality for patients at risk for restenosis.

References

  1. Bhatt D, Topol E. Current role of platelet GP IIb/IIIa inhibitors in acute coronary syndromes. JAMA. 2000;284:1549–1558.[Abstract/Free Full Text]
  2. Sabatine M, Jang I. The use of glycoprotein IIb/IIIa inhibitors in patients with coronary artery disease. Am J Med. 2000;109:224–237.[Medline] [Order article via Infotrieve]
  3. Cipollone F, Marini M, Fazia M, Pini B, Iezzi A, Reale M, Paloscia L, Materazzo G, D’Annunzio E, Conti P, Chiarelli F, Cuccurullo F, Mezzetti A. Elevated circulating levels of monocyte chemoattractant protein-1 in patients with restenosis after coronary angioplasty. Arterioscler Thromb Vasc Biol. 2001;21:327–334.[Abstract/Free Full Text]
  4. Rollins B. Chemokines. Blood. 1997;90:909–928.[Free Full Text]
  5. Luster A. Chemokines: chemotactic cytokines that mediate inflammation. N Engl J Med. 1998;338:436–445.[Free Full Text]
  6. Taub D. Chemokine-leukocyte interactions. Cytokine Growth Factor Rev. 1996;7:355–381.[Medline] [Order article via Infotrieve]
  7. Yla-Herttuala S, Lifton B, Rosenfeld M, Sarkioja T, Yoshimura T, Leonard E, Witztum J, Steinberg D. Expression of MCP-1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A.. 1991;88:5252–5256.[Abstract/Free Full Text]
  8. Kowala M, Recce R, Beyer S, Gu C, Valentine M. Characterization of atherosclerosis in LDL receptor knockout mice: macrophage accumulation correlates with rapid and sustained expression of aortic MCP-1/JE. Atherosclerosis. 2000;149:323–330.[Medline] [Order article via Infotrieve]
  9. Aiello R, Bourassa P-A, Lindsey S, Seng W, Natoli E, Rollins B, Milos P. MCP-1 accelerates atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 1999;19:1518–1525.[Abstract/Free Full Text]
  10. Nelken N, Coughlin S, Gordon D, Wilcox J. MCP-1 in human atheromatous plaques. J Clin Invest. 1991;88:1121–1127.
  11. Boring L, Gosling J, Cleary M, Charo I. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998;394:894–897.[Medline] [Order article via Infotrieve]
  12. Yu X, Dluz S, Graves D, Zhang L, Antoniates H, Hollander W, Prusty S, Valente A, Schwartz C, Sonenshein G. Elevated expression of MCP-1 by vascular smooth muscle cells in hypercholesterolemic primates. Proc Natl Acad Sci U S A.. 1992;89:6953–6957.[Abstract/Free Full Text]
  13. Matsumori A, Furukawa Y, Hashimoto T, Yoshida A, Ono K, Shioi T, Okada M, Iwasaki A, Nishio R, Matsushima K, Sasayama S. Plasma levels of monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 are elevated in patients with acute myocardial infarction. J Mol Cell Cardiol. 1997;29:419–423.[Medline] [Order article via Infotrieve]
  14. Aukrust P, Ueland T, Muller F, Andreassen A, Nordoy I, Aas H, Kjekshus J, Simonsen S, Froland S, Gullestad L. Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circulation. 1998;97:1136–1143.[Abstract/Free Full Text]
  15. Flory C, Jones M, Warren J. Pulmonary granuloma formation in the rat is partially dependent on MCP-1. Lab Invest. 1993;69:396–404.[Medline] [Order article via Infotrieve]
  16. Wada K, Yokohama H, Furuichi K, Kobayashi K-I, Harada K, Naruto M, Su S-B, Akiyama M, Mukaida N, Matsushima K. Intervention of crescentic glomerulonephritis by antibodies to MCAF/MCP-1. FASEB J. 1996;10:1418–1425.[Abstract]
  17. Gong J, Ratkay L, Waterfield J, Clark-Lewis I. An antagonist of MCP-1 inhibits arthritis in the MRL-lpr mouse model. J Exp Med. 1997;186:131–137.[Abstract/Free Full Text]
  18. Berman J, Guida M, Warren J, Amat J, Brosnan C. Localization of MCP-1 expression in the central nervous system in EAE and trauma in the rat. J Immunol. 1996;156:3017–3023.[Abstract]
  19. Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, Pinzani M, Romanelli R, Laffi G, Gentilini P. Increased expression of MCP-1 during active hepatic fibrogenesis. Am J Pathol. 1998;152:423–430.[Abstract]
  20. Carr M, Roth S, Luther E, Rose S, Springer T. MCP-1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994;91:3652–3656.[Abstract/Free Full Text]
  21. Siveke J, Hamann A. Cutting edge: T helper 1 and T helper 2 cells respond differentially to chemokines. J Immunol. 1998;160:550–554.[Abstract/Free Full Text]
  22. Maghazachi A, al-Aoukaty A, Schall T. C-C chemokines induce the chemotaxis of NK, and IL-2-activated NK cells: role for G proteins. J Immunol. 1994;153:4969–4977.[Abstract]
  23. Alavena P, Bianchi G, Zhou D, vanDamme J, Jilek P, Sozzani S, Matovani A. Induction of natural killer cell migration by MCP-1, -2, and -3. Eur J Immunol. 1994;24:3233–3236.[Medline] [Order article via Infotrieve]
  24. Kunkel S. Through the looking glass: the diverse in vivo activities of chemokines. J Clin Invest. 1999;104:1333–1334.[Medline] [Order article via Infotrieve]
  25. Gu L, Tseng S, Rollins B. Monocyte chemoattractant protein-1. Chem Immunol. 1999;72:7–29.[Medline] [Order article via Infotrieve]
  26. Schechter A, Rollins B, Zhang Y, Charo I, Fallon J, Rossikhina M, Giesen P, Nemerson Y, Taubman M. Tissue factor is induced by MCP-1 in human aortic smooth muscle and THP-1 cells. J Biol Chem. 1997;272:28568–28573.[Abstract/Free Full Text]
  27. Ernofsson M, Siegbahn A. PDGF-BB and MCP-1 induce peripheral blood monocytes to express tissue factor. Thromb Res. 1996;83:307–320.[Medline] [Order article via Infotrieve]
  28. Ikeda U, Ikeda M, Seino Y, Taiahashi M, Kasahara T, Kano S, Shimada K. Expression of ICAM-1 on rat vascular smooth muscle cells by pro-inflammatory cytokines. Atherosclerosis. 1993;104:61–68.[Medline] [Order article via Infotrieve]
  29. Rollins B, Morrison E, Stiles C. Cloning and expression of JE, a gene inducible by PDGF and whose product has cytokine-like properties. Proc Natl Acad Sci U S A. 1988;85:3738–3742.[Abstract/Free Full Text]
  30. Kolattukudy P, Quach T, Bergese S, Breckenridge S, Hensley J, Altschuld R, Gordillo G, Klenotic S, Orosz C, Parker-Thornburg J. Myocarditis induced by targeted expression of the MCP-1 gene in murine cardiac muscle. Am J Pathol. 1998;152:101–111.[Abstract]
  31. Fuentes M, Durham S, Swerdel M, Lewin A, Barton D, Megill J, Bravo R, Lira S. Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of MCP-1. J Immunol. 1995;155:5769–5776.[Abstract]
  32. Grewal I, Rutledge B, Fiorillo J, Gu L, Gladue R, Flavell R, Rollins B. Transgenic MCP-1 in pancreatic islets produces monocyte-rich insulitis without diabetes: abrogation by a second transgene expressing systemic MCP-1. J Immunol. 1997;159:401–408.[Abstract]
  33. Rollins B. MCP-1: a potential regulator of monocyte recruitment in inflammatory disease. Mol Med Today. 1996;5:198–204.
  34. Jones M, Mulligan M, Flory C, Ward P, Warren J. Potential role of MCP-1/JE in monocyte/macrophage-dependent IgA immune complex alveolitis in the rat. J Immunol. 1992;149:2147–2154.[Abstract]
  35. Gu L, Okada Y, Clinton S, Sukhova G, Libby P, Rollins B. Absence of MCP-1 reduces atherosclerosis in LDL receptor-deficient mice. Mol Cell. 1998;2:275–281.[Medline] [Order article via Infotrieve]
  36. Kumar A, Ballantyne C, Michael L, Kukielka G, Youker K, Lindsey M, Hawkins H, Birdsall H, MacKay C, LaRosa G, Rossen R, Smith C, Entman M. Induction of MCP-1 in the small veins of the ischemic and reperfused canine myocardium. Circulation. 1997;95:693–700.[Abstract/Free Full Text]
  37. Herschman H. Primary response genes induced by growth factors and tumor promoters. Annu Rev Biochem. 1991;60:281–319.[Medline] [Order article via Infotrieve]
  38. Taubman M, Rollins B, Poon M, Marmur J, Green R, Berk B, Nadal-Ginard B. JE mRNA accumulates rapidly in aortic injury and in PDGF-stimulated vascular smooth muscle cells. Circ Res. 1992;70:314–325.[Abstract/Free Full Text]
  39. Furukawa Y, Matsumori A, Ohashi N, Shioi T, Ono K, Harada A, Matsushima K, Sasayama S. Anti-MCP-1/MCAF antibody inhibits neointimal hyperplasia in injured rat carotid arteries. Circ Res. 1999;84:306–314.[Abstract/Free Full Text]
  40. Wysocki S, Zheng M, Smith A, Lamawansa M, Iacopetta B, Rob T, Papadimitriou J, House A, Norman P. MCP-1 gene expression in injured iliac artery coincides with early appearance of infiltrating monocyte/macrophages. J Cell Biochem. 1996;62:303–313.[Medline] [Order article via Infotrieve]
  41. Collins T. Endothelial nuclear factor {kappa}B and the initiation of the atherosclerotic lesion. Lab Invest. 1993;68:499–508.[Medline] [Order article via Infotrieve]
  42. Gautam S, Pindolia K, Noth C, Janakiraman N, Xu Y, Chapman R. Chemokine gene expression in bone marrow stromal cells: down-regulation with sodium salicylate. Blood. 1995;86:2541–2550.[Abstract/Free Full Text]
  43. Santiago F, Lowe H, Kavurma M, Chesterman C, Baker A, Atkins D, Khachigian L. New DNA enzyme targeting Egr-1 mRNA inhibits vascular smooth muscle proliferation and regrowth after injury. Nat Med. 1999;5:1264–1269.[Medline] [Order article via Infotrieve]
  44. Yan S-F, Fujita T, Lu J, Okada K, Zou Y-S, Mackman N, Pinsky D, Stern D. Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress. Nat Med. 2000;6:1355–1361.[Medline] [Order article via Infotrieve]
  45. Lee H, Shi W, Tontonoz P, Wang S, Subbanagounder G, Hedrick C, Hama S, Borromeo C, Evans R, Berliner J, Nagy L. Role for PPAR-{alpha} in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells. Circ Res. 2000;87:516–521.[Abstract/Free Full Text]
  46. Bogdanov V, Poon M, Taubman M. PDGF-specific regulation of the JE promoter in rat aortic smooth muscle cells. J Biol Chem. 1998;273:24932–24938.[Abstract/Free Full Text]
  47. Tsao P, Yang B-y, Buitrago R, Shyy J, Cooke J. Nitric oxide regulates MCP-1. Circulation. 1997;96:934–940.[Abstract/Free Full Text]
  48. Tomita H, Egashira K, Kubo-Inoue M, Usui M, Koyanagi M, Shimogawa H, Takeya M, Yoshimura T, Takeshita A. Inhibition of NO synthesis induces inflammatory changes in MCP-1 expression in rat hearts and vessels. Arterioscler Thromb Vasc Biol. 1998;18:1456–1464.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Pathol.Home page
K. A. Nath, S. K. R. Kanakiriya, J. P. Grande, A. J. Croatt, and Z. S. Katusic
Increased Venous Proinflammatory Gene Expression and Intimal Hyperplasia in an Aorto-Caval Fistula Model in the Rat
Am. J. Pathol., June 1, 2003; 162(6): 2079 - 2090.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
S. K. R. Kanakiriya, A. J. Croatt, J. J. Haggard, J. R. Ingelfinger, S.-S. Tang, J. Alam, and K. A. Nath
Heme: a novel inducer of MCP-1 through HO-dependent and HO-independent mechanisms
Am J Physiol Renal Physiol, March 1, 2003; 284(3): F546 - F554.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
A. S. Weyrich, S. M. Prescott, and G. A. Zimmerman
Platelets, Endothelial Cells, Inflammatory Chemokines, and Restenosis: Complex Signaling in the Vascular Play Book
Circulation, September 17, 2002; 106(12): 1433 - 1435.
[Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schmidt, A. M.
Right arrow Articles by Stern, D. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schmidt, A. M.
Right arrow Articles by Stern, D. M.

ATVB Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2001 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.