(Circulation. 1997;95:1355-1356.)
© 1997 American Heart Association, Inc.
A Role for Intercellular Adhesion Molecule-1 in Restenosis
the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Dr Edward F. Plow, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
Key Words: Editorials • cells • angioplasty • intercellular adhesion molecule-1
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Introduction |
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With more than 30% of patients requiring an additional intervention within 1 year after PTCA, restenosis continues to be a clinical complication of enormous importance.1 Because the nature of the causative event, neointimal hyperplasia arising from vascular injury, and the timing of the initiating event, the time of PTCA, are well defined, it seems that restenosis should be a ready target for treatment and prevention. Nevertheless, restenosis has remained stubbornly resistant to therapy for almost 20 years. This contradiction implies that our knowledge of the molecular and cellular mechanisms underlying restenosis is inadequate and/or that the therapeutic targets selected thus far have not been optimal. In the present issue of Circulation, Yasukawa et al2 examine the role of ICAM-1 in intimal hyperplasia. These investigators show that ICAM-1 is expressed early and intensely in rat carotid arteries after balloon injury and that an MAb to ICAM-1 significantly suppresses intimal hyperplasia in the rat model of restenosis. Thus, this article provides new insights into the basic changes that occur within developing restenotic lesions, implicates ICAM-1 in the mechanisms leading to intimal hyperplasia, and identifies a new candidate target to consider for the treatment of restenosis.
ICAM-1 is a highly glycosylated cell surface protein of 95 kD. It is expressed at variable levels on EC, SMC, fibroblasts, several tumor cell lines, and circulating leukocytes.3 On cultured EC and SMC, the levels of ICAM-1 are dramatically upregulated on treatment with inflammatory mediators, such as TNF-
, interferon-
, interleukin-1, and bacterial lipopolysaccharide.4 5 TNF- augments new synthesis and cell-surface expression of ICAM-1 within 4 hours, and the levels remain high for >48 hours. The time course of ICAM-1 expression on EC parallels that of leukocyte infiltration during an inflammatory response.5 Soluble forms of ICAM-1 have also been detected in several inflammatory conditions,6 but the mechanism of ICAM-1 release and the relationship of this form to pathogenesis remain unclear.
ICAM-1 is a member of an immunoglobulin-like superfamily of proteins, which include, among others, VCAM-1, PECAM-1, and ICAM-2.3 ICAM-1 contains five immunoglobulin-like motifs in its extracellular domain, which is followed by a single transmembrane region and a short cytoplasmic tail. This cytoplasmic segment of ICAM-1 reacts with cytoskeletal proteins and is likely to be involved in signal transduction.7 Each immunoglobulin motif is a disulfide-linked unit of 
80 to 90 amino acids that forms an unique, seven–anti-parallel ß-sheet–like structure.3 8
The major known functions of ICAM-1 relate to its role in cell adhesion and migration. ICAM-1 is a counterreceptor for the ß2 leukocyte integrins LFA-1 (Lß2, CD11a/CD18) and MAC-1 (Mß2, CD11b/CD18), and their engagement results in leukocyte adhesion and transmigration through EC. ICAM-1/LFA-1 interactions are viewed as being particularly important for leukocyte transmigration.9 10 11 In addition to direct interactions between ICAM-1 and the ß2 integrins, fibrinogen is a ligand for both ICAM-1 and MAC-1.11 12 Therefore, fibrinogen can enhance leukocyte adhesion to EC by bridging these cells in an ICAM-1–dependent manner. In addition, ICAM-1 is a receptor for several major subtypes of rhinoviruses (the common cold), and plasmodium-infected erythrocytes can bind to EC via ICAM-1.3 8 The first two immunoglobulin motifs of ICAM-1 are the recognition regions for LFA-1, rhinoviruses, plasmodium-infected erythrocytes, and fibrinogen, whereas the third immunoglobulin motif is involved in binding Mß2. Rotary shadowing images13 of ICAM-1 reveal that the first three immunoglobulin motifs extend away from the plasma membrane of cells, placing them in a suitable posture to function in cell adhesion and migration.
In their article, Yasukawa et al2 first examine the expression of ICAM-1 over time after balloon injury by immunohistochemical staining and then demonstrate that the administration of an ICAM-1 MAb to animals significantly suppresses the extent of neointimal formation. ICAM-1 is shown to be expressed extensively and intensely by medial SMC at 1 to 2 days after balloon injury to rat carotid arteries. At 5 to 7 days, the SMC in the developing neointima showed some positivity for ICAM-1, as did the regenerating EC. The expression of ICAM-1 by these latter cells was more intense than that observed for uninjured EC and is consistent with the activated phenotype of the regenerating EC. Importantly, the ICAM-1 MAb did not reduce the accumulation of monocytes/macrophages within the injured vessels. Therefore, inhibition of ICAM-1–dependent monocyte/macrophage migratory functions was probably not the basis for the therapeutic benefit of the ICAM-1 MAb. Because the MAb was administered for only the first 6 days after balloon injury, its effect most likely depends on its neutralization of ICAM-1 functions on the SMC, although the particular SMC target, medial or intimal, cannot be determined.
When Yasukawa and colleagues administered the ICAM-1 MAb over 6 consecutive days after balloon injury to rat carotid arteries, neointimal formation, as assessed morphometrically, was significantly (P<.05) suppressed compared with that of control animals. The suppressive effect of the ICAM-1 MAb was 50% whether quantified by measurement of intima area or intimal/medial ratio. The control groups used in this analysis merit special comment. Included as a control was a MAb that reacts with an unrelated SMC cell-surface glycoprotein. Thus, reaction of a MAb with SMC does not in itself paralyze SMC functions and blunt neointima formation. More importantly, a MAb to LFA-1, known to block the adhesive function of this ß2 integrin, did not affect neointima formation and did not enhance the inhibitory activity of the ICAM-1 MAb. As noted above, most of the clearly demonstrable functions of ICAM-1 in vivo depend on its interaction with LFA-1. Thus, many of the effects of ICAM-1 MAbs, including their influence on cardiac allograft rejection14 and myocardial reperfusion injury,15 can be recapitulated or augmented by LFA-1 MAbs. This was not the case in the study by Yasukawa et al.2 This observation raises the possibility that an LFA-1–independent function of ICAM-1 contributes to its role in restenosis. Furthermore, because monocyte/macrophage accumulation was not affected by the ICAM-1 MAb, MAC-1/ICAM-1 interactions also were probably not the target. These exclusions leave open the intriguing possibility that other ICAM-1–dependent events play a major role in restenosis. The nature of these events remains to be identified. Recently, we have found that the capacity of fibrinogen to enhance cell proliferation is dependent on ICAM-1 (E.E. Gardiner and S.E. D'Souza, unpublished data, 1997).
Any therapeutic agent that exerts a significant effect on the intimal formation in the rat carotid injury model must be considered cautiously. Many such agents have been proved to be ineffective in larger animal models and have been uniformly disappointing when tested in humans. Nevertheless, we should not become so skeptical as to dismiss ICAM-1 as a potential therapeutic target a priori. The study by Yasukawa et al2 should serve as a signal for systematic evaluation of ICAM-1 as a target for restenosis. In the EPIC Trial,16 a MAb to ß3 integrins was shown to reduce the need for repeat procedures in patients undergoing PTCA. This trial, together with the Yasukawa study and other studies,17 suggests that cell migration and adhesion and the use of MAbs to block these responses may represent valid approaches to reduction of the complications of PTCA. Above all, the present study suggests that it will be important to develop further an understanding of the role of ICAM-1 in SMC and EC migration and proliferation. Within such studies may lie new clues to the causes and treatment of restenosis.
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Selected Abbreviations and Acronyms |
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The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
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References |
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TopIntroductionReferences |
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2.
Yasukawa H, Imaizumi T, Matsuoka H, Nakashima A, Morimatsu M. Inhibition of intimal hyperplasia after balloon injury by antibodies to intercellular adhesion molecule-1 and lymphocyte function–associated antigen-1. Circulation. 1997;95:1515-1522.
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14.
Isobe M, Yagita H, Okumura K, Ihara A. Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1. Science. 1992;255:1125-1127.
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Choi ET, Engel L, Callow AD, Sun S, Trachtenberg J, Santoro S, Ryan US. Inhibition of neointimal hyperplasia by blocking Vß3 integrin with a small peptide antagonist GpenGRGDSPCA. J Vasc Surg. 1994;19:125-134.[Medline]
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