© 2001 American Heart Association, Inc.
Editorial |
Chemokines on the Rise
MCP-1 and Restenosis
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-
B and Egr-1 in the injured vessel
wall.41 42 43 44
In addition, a role for peroxisome proliferator-activated
receptor-
,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. 1
). 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
|
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.
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.
4.
Rollins B.
Chemokines. Blood. 1997;90:909–928.
5.
Luster A.
Chemokines: chemotactic cytokines that mediate inflammation.
N Engl J Med. 1998;338:436–445.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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- in oxidized
phospholipid-induced synthesis of monocyte chemotactic protein-1 and
interleukin-8 by endothelial cells.
Circ Res. 2000;87:516–521.
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.
47.
Tsao P, Yang B-y,
Buitrago R, Shyy J, Cooke J. Nitric oxide regulates MCP-1.
Circulation. 1997;96:934–940.
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.
This article has been cited by other articles:
 |
|
 |
|
  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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||