Modulation of adhesion molecule expression on endothelial cells: to be or not to be?

Abstract

Journal of Thrombosis and HaemostasisVolume 1, Issue 11 p. 2280-2282 Free Access Modulation of adhesion molecule expression on endothelial cells: to be or not to be? P. L. Meroni, P. L. Meroni Allergy, Clinical Immunology & Rheumatology Unit, IRCCS Istituto Auxologico Italiano, Department of Internal Medicine, Milan, Italy; andSearch for more papers by this authorE. Tremoli, E. Tremoli Laboratorio di Biologia Cellulare e di Biochimica dell'Aterosclerosi, IRCCS Centro Cardiologico Monzino, Department of Pharmacological Sciences, University of Milan, Milan, ItalySearch for more papers by this author P. L. Meroni, P. L. Meroni Allergy, Clinical Immunology & Rheumatology Unit, IRCCS Istituto Auxologico Italiano, Department of Internal Medicine, Milan, Italy; andSearch for more papers by this authorE. Tremoli, E. Tremoli Laboratorio di Biologia Cellulare e di Biochimica dell'Aterosclerosi, IRCCS Centro Cardiologico Monzino, Department of Pharmacological Sciences, University of Milan, Milan, ItalySearch for more papers by this author First published: 18 November 2003 https://doi.org/10.1046/j.1538-7836.2003.00487.xCitations: 4 P. L. Meroni, Allergy, Clinical Immunology & Rheumatology Unit, IRCCS Istituto Auxologico Italiano, Via L. Ariosto, 13, 20145 Milan, Italy. Fax: +39 02 61911 2559; e-mail: pierluigi.meroni@unimi.it AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Endothelial activation/damage in response to injury might end in the expression of a proadhesive and a pro-inflammatory phenotype in several pathological processes including autoimmune vasculitis and vasculopathies. In both cases endothelial cells upregulate the expression of adhesion molecules (ADM) on their cell membranes, so favoring an enhanced leukocyte adhesion and transmigration, and are induced to increase the synthesis and secretion of pro-inflammatory soluble mediators such as cytokines, chemokines and growth factors. While the phenomenon is well documented in autoimmune vasculitis, it does occur to a lesser extent in vasculopathies also [1]. Evidence from a broad range of studies demonstrates that atherosclerotic vasculopathy involves inflammatory responses by endothelial cells. Actually, according to the oxidation hypothesis, low-density lipoproteins retained in the intima undergo oxidative modification and can induce ADM expression, pro-inflammatory cytokines/chemokines, and other mediators of inflammation in macrophages and vascular wall cells. The recruitment and adhesion of circulating leukocytes in inflamed vessel walls is thought to represent an early event in atherosclerosis. Adhered leukocytes then infiltrate the vessel wall, participating in plaque formation as well as favoring its stability or instability [2, 3]. Therapeutic interventions aimed at counteracting such events were thought to be useful both in primary and in secondary prevention. Different therapeutic approaches, including drugs, can decrease serum lipid levels, their intima deposition and eventually inhibit the atherosclerotic process with a significant reduction in cardiovascular events [4]. Among the several drugs able to lower serum lipid levels, statins in particular have been shown to be effective in reducing mortality and morbidity in large clinical trials with dyslipidemic patients [5]. However, critical analysis of these studies suggested that the benefits of such therapy could not be fully explained on the basis of the simple reduction in plasma cholesterol levels [6]. The demonstration that C-reactive protein (CRP) plasma levels were decreased after statin therapy in hypercholesterolemic as well as in normocholesterolemic patients focused the attention on its potential anti-inflammatory activity [3, 7]. In the same patient groups a decrease of pro-inflammatory cytokine [mainly interleukin (IL)-6 and tumor necrosis factor (TNF)-α] serum levels was also found, strongly suggesting a close cause–effect relationship between the reduction of CRP and cytokine secretion [7]. Furthermore, the anti-inflammatory activity of statins and particularly their ability to affect leukocyte adhesion and transmigration—independently of the lipid-lowering activity—has been recently demonstrated in in vivo experimental animal models of localized acute inflammation [8-11] (Fischetti et al., unpubl. data). The endothelial pro-adhesive phenotype is characterized by ADM upregulation followed by an increased shedding of soluble isoforms into the circulation; actually, elevated plasma levels of soluble ADMs have been reported in active systemic vasculitis [12, 13]. It has been demonstrated that dyslipidemia also enhances ADM expression and release of their soluble isoforms [3]. Interestingly, there are clinical reports showing that statin administration might reduce the circulating levels of soluble ADM, although differences in intensity and efficacy of the different compounds were reported [3]. However, besides E-selectin, most of the ADMs [i.e. intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, P-selectin] are expressed by different cell types involved in the inflammatory process associated with atherosclerosis [12, 13]. For example, activated peripheral blood mononuclear cells rather than endothelium might be responsible for soluble ICAM-1 and/or VCAM-1 release. Accordingly, there is an agreement among different in vivo and in vitro studies on the ability of statins to downregulate monocyte activation and their ADM expression [6, 14-16]. Although such findings support a potential beneficial effect of statins in preventing the infiltration of vessel walls by inflammatory cells, it is difficult to identify which cell type is the pharmacological target. On the other hand, it is widely accepted that statins can directly affect the pro-inflammatory responses of endothelial cells in vitro[6]. The question could be theoretically addressed by experiments in which endothelial ADM upregulation is evaluated in the presence of the drug. Human endothelial cells in culture in fact do not express significant amounts of E-selectin and VCAM-1, with just slight constitutive expression of ICAM-1 in resting conditions; however, cell activation by several agonists (pro-inflammatory cytokines, autoantibodies, lipopolysaccharide, etc.) can upregulate ADM expression with different time kinetics [17]. In fact, some groups reported that ADM upregulation on endothelial cell membranes by pro-inflammatory cytokines or by autoantibodies was inhibited when cell monolayers were incubated in the presence of statins [14, 18-23]. In the present issue, Dimitrova et al. report a study showing a paradoxical enhancement of ADM expression on human endothelial cells (EC) [from umbilical cord (HUVEC) and saphenous vein] by statins [24]. Such an enhancement would favor an eventual inflammatory cell infiltrate into the plaque, an effect apparently contrary to the supposed protective effect of statins. Moreover, comparable findings were reported by other groups, showing that simvastatin, lovastatin and atorvastatin increased ADM expression on HUVEC after activation with pro-inflammatory cytokines [25-27], in contrast to the previously mentioned inhibition [8-23]. The discrepancy among these findings is even more striking since protein expression is associated with specific mRNA reduction or enhancement, depending on whether ADM inhibition or upregulation was found. In just one study, authors described reduced mRNA levels for VCAM-1 and E-selectin with decreased VCAM-1 but increased E-selectin surface expression, apparently consequent to its shedding inhibition [19]. Interestingly, the inhibitory or enhancing effect of statins was associated with the increase or reduction of nuclear factor (NF)-κB activation, respectively, and was reverted by the addition of mevalonate. As a whole, these findings suggest that, independently of the eventual effect, ADM modulation by statins is through the mevalonate-dependent pathway and NF-κB translocation, as also elegantly confirmed and expanded by the results of Dimitrova et al. [24] (Fig. 1). Figure 1Open in figure viewerPowerPoint Potential mechanisms by which statins can affect endothelial cell adhesion molecule expression/function: (1) by inhibiting leukocyte function antigen-1 binding with the ligand; (2) by blocking E-selectin shedding; (3) by affecting adhesion molecule cell membrane expression through (4) NF-κB activation and (5) mRNA transcription. There are several reasons for these contrasting results: (i) differences in techniques of evaluating ADM expression; (ii) the use of different compounds of the statin family; and (iii) the diverse agonists employed in activating the cells. Studies performed with the same statins and with a wide panel of techniques able to investigate ADM expression at protein and mRNA levels and the involved signaling pathways at the same time, would be useful to obtain definite results on the direct ability of statins to affect ADM upregulation by activated endothelial cells. It should be pointed out that statins can also directly interfere with the interaction between ICAM-1 and its natural ligand (integrin αLβ2) by an alternative mechanism that does not require protein synthesis inhibition [28] (Fig. 1). 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