Elsevier

Atherosclerosis

Volume 170, Issue 2, October 2003, Pages 191-203
Atherosclerosis

Review
Adhesion molecules and atherosclerosis

https://doi.org/10.1016/S0021-9150(03)00097-2Get rights and content

Abstract

One early phase of atherosclerosis involves the recruitment of inflammatory cells from the circulation and their transendothelial migration. This process is predominantly mediated by cellular adhesion molecules, which are expressed on the vascular endothelium and on circulating leukocytes in response to several inflammatory stimuli. Selectins (P, E and L) and their ligands (mainly P-selectin ligand) are involved in the rolling and tethering of leukocytes on the vascular wall. Intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecules (VCAM-1), as well as some of the integrins, induce firm adhesion of inflammatory cells at the vascular surface, whereas platelet endothelial cellular adhesion molecules (PECAM-1) are involved in extravasation of cells from the blood compartment into the vessel and underlying tissue. For most of the cellular adhesion molecules, except integrins, soluble forms have been identified in the circulation although their origins are not fully understood. Several lines of evidence support a crucial role of adhesion molecules in the development of atherosclerosis and plaque instability. Expression of VCAM-1, ICAM-1 and L-selectin has been consistently observed in atherosclerotic plaques. There is accumulating evidence from prospective studies for a predictive role of elevated circulating levels of sICAM-1 in initially healthy people, and of sVCAM-1 in patients at high risk or with overt CAD. A large number of common polymorphisms has been identified in the genes encoding the different adhesion molecules, but studies investigating their relationship either with soluble forms or with CAD are still sparse and often based on small samples. Further research is needed to firmly establish the potential clinical and therapeutic utilities of (soluble) adhesion molecules, but results in both fields hold the promise that in future, adhesion molecules might add information for clinical risk prediction and serve as therapeutic targets.

Introduction

During recent years, the role of inflammation in atherosclerosis has been increasingly recognized [1], [2]. Evidence for the importance of inflammation in atherosclerosis have been adduced from both basic science and clinical research. A better understanding of the mechanisms linking inflammatory processes to atherogenesis and plaque instability might have important clinical consequences for the identification of high-risk patients and the development of new anti-inflammatory therapies, especially during acute event.

One early phase of atherosclerosis involves the recruitment of inflammatory cells from the circulation and their transendothelial migration [3]. The basic science of inflammation biology applied to atherosclerosis has afforded considerable new insight into the mechanisms underlying the recruitment of leukocytes. This process is predominantly mediated by cellular adhesion molecules, which are expressed on the vascular endothelium and on circulating leukocytes in response to several inflammatory stimuli [4]. Several lines of evidence support a role for cell adhesion molecules in atherogenesis. In humans, focal expression of adhesion molecules has been consistently observed in atheroslerotic plaques [5], [6], [7], [8], [9]. Levels of soluble adhesion molecules have been postulated to be useful risk predictors of cardiovascular events in healthy populations and various settings of disease, even though their pathological role remains uncertain [10]. Information gained from human genetic studies and animal models also supports the role of adhesion molecules as important players in the atherogenic process. The present review tries to summarize the recent knowledge on this topic from a basic science, clinical and genetic points of view.

Section snippets

Biology of cellular adhesion molecules

Cellular adhesion molecules are, according to the definition of the Gene Ontology Consortium (http://www.geneontology.org/) “molecules expressed on the surface of a cell that mediate the adhesion of the cell to other cells or to the extracellular matrix”. These proteins are playing numerous crucial functions at the interface of a cell and its environment, whether this environment is another cell, from a similar or different cell type, the extracellular matrix or even sometimes soluble elements.

Rare mutations responsible for monogenic diseases

Some rare monogenic disorders due to mutations in genes encoding adhesion molecules have been described. Patients affected by leukocyte adhesion deficiency (LAD), a rare autosomal recessive disorder (about 200 patients reported so far), present with multiple, life-threatening, chronic bacterial infections. They have an important defect in inflammatory/immune cell recruitment. The most severe form, LAD I, is the result of a complete deficiency of the integrin β2 chain, whereas the milder form,

Soluble adhesion molecules and atherosclerosis

The recognition that inflammation plays a role in all stages of the atherosclerotic disease process [2] has stimulated the search for circulating proteins reflecting the process of inflammation of the vessel wall and indicating patients at high risk for future cardiovascular events. In the recent years, special attention has been paid to the potential value of soluble adhesion molecules as biomarkers for CAD [45]. As outlined in Section 2, the origins of soluble forms are not entirely clear,

Polymorphisms of adhesion molecule genes and soluble form levels

Studies investigating the association between polymorphisms of the genes encoding the different adhesion molecules and their circulating levels are sparse. In the AtheroGene study, the T715P polymorphism as well as two common polymorphisms of the 5′-flanking region (C-2123G and A-1969G) were shown to strongly influence serum P-selectin levels [47]. Carriers of the P715 allele had lower sP-selectin levels than homozygotes for the T715 allele. Furthermore, an interaction between the T715P

Selectin genes

Two non-synonymous polymorphisms of the E-selectin gene (S128R and L554F) have been mainly investigated. The S128R polymorphism was associated with early atherosclerosis [115], coronary calcification [116], and restenosis after angioplasty [117], while the L554F polymorphism was found associated with early atherosclerosis [118] and hypertension [119]. Functional studies have demonstrated a reduced strength of adhesion associated with the R128 allele as well as a diminished release of soluble

Cell adhesion molecules: useful clinical predictors and therapeutical targets?

Information accumulating on cell adhesion molecules during the past years from basic and clinical researches warrants attention for several reasons. First, circulating levels of soluble adhesion molecules may be useful tools for stratifying disease severity or prognosis. Second, results from epidemiological, clinical and genetic studies may provide new insights into the pathophysiology of atherosclerosis and plaque instability, and third, these data might encourage further therapies directed

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