| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Special Articles |
Haemostasis, Thrombosis and Vascular Biology Unit University Department of Medicine City Hospital Birmingham B18 7QH, United Kingdom
Address correspondence and requests for reprints to: Gregory Y. H. Lip, University Department of Medicine, City Hospital, Haemostasis, Thrombosis and Vascular Biology, Dudley Road, Birmingham B18 7QH, United Kingdom.
 |
Introduction |
|---|
 Top Introduction References |
|---|
However, these aspects may be inter-related because soluble forms of these adhesion molecules themselves may potentially interfere with leukocyte/endothelial cell interactions, at least in vitro (8, 9). Despite this, soluble adhesion molecules may still be useful in dissecting the pathophysiological events in cardiovascular disease, as it may be presumed that changes in levels may relate to activation or damage to various cells, such as the platelet and endothelium.
The selectin family of adhesion molecules has three members. Soluble P-selectin is believed to be the product of activated platelets, although the endothelium displays a membrane-bound form (10, 11). Increased levels are found in a number of conditions, including thrombotic disorders, diabetes, and ischaemic heart disease, and in the latter, raised levels predicted adverse events (12, 13, 14). Although increased levels of soluble E-selectin are the result of cytokine activation of endothelial cells in vitro (15), and raised levels in the plasma have been reported in variant (but not stable) angina (16) and in ischaemic heart disease (17), such raised levels do not seem to predict adverse events cardiovascular events (18) but do predict progression of peripheral atherosclerosis (19). It is still unclear whether or not levels of soluble L-selectin, derived from leukocytes, are altered in cardiovascular diseases although we have been unable to find differences between patients with peripheral atherosclerosis and healthy controls (20). However, Siminiak et al. (21) recently reported raised levels within 1 h to 3 days following admission for acute myocardial infarction, and Haught et al. (22) found low levels in stable and unstable angina, and in acute myocardial infarction.
The second major group of adhesion molecules belongs to the immunoglobulin supergene family, and three of its members warrant attention. Soluble intercellular adhesion molecule-1 (sICAM-1) is a likely product of many cells, including the endothelium and leukocytes. Also influenced by inflammatory cytokines in vitro (15), raised levels are found in many conditions, including angina (16) and both coronary artery disease and peripheral artery disease (23). However, although raised levels in healthy men predict adverse events (6), the association is weak when there is a background of existing atherosclerosis (7). Conversely, vascular cell adhesion molecule-1 (sVCAM-1) does not seem to be increased in the plasma of patients with angina or coronary artery disease (16, 23): neither do levels predict adverse outcome (7). However, levels do rise slowly (reaching a peak on day 3) after an acute myocardial infarction and are moderately raised in some forms of peripheral atherosclerosis, where levels correlated with the extent of disease (24, 25). Soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) may arise from many cells, including endothelial cells, platelets, and leukocytes. Nevertheless, we have been unable to find differences in the plasma of patients with coronary artery disease or peripheral artery disease compared with controls (26).
It has long been proposed that damage to the endothelium is important in the development and/or progression of atherosclerosis (27), and increased levels of endothelial cell markers in the plasma of subjects who go onto suffer adverse cardiovascular events support this concept (28, 29). Among the most commonly used endothelial cell markers are von Willebrand factor, soluble thrombomodulin, and soluble E-selectin (17, 18, 19). Increased levels of sICAM and sVCAM are often taken to imply damage and/or stimulation of the endothelium, but the expression of these molecules on smooth muscle cells, leukocytes, and tumor cells suggests some caution may be necessary (30, 31, 32). However, despite these caveats, increased levels of all these molecules in a variety of cardiovascular, inflammatory, and neoplastic diseases are well established, and in many cases may be useful in predicting clinical outcome, but the precise mechanisms for these increased levels are often unclear.
Diabetes is a case in point. Numerous groups have shown raised levels of various markers in both type 1 and type 2 diabetes mellitus (reviewed in Refs. 33, 34), and it, therefore, follows that these changes may be related to the profound alterations in the metabolic homeostasis in the patients. Among the primary biochemical changes in diabetes are, of course, disturbances in blood glucose, insulin, and lipids, any of which may, in theory, be responsible for changes in endothelial and other markers, blood pressure control (leading to hypertension), and renal integrity (leading to albuminuria and renal failure) (35). Therefore, the pursuit of the mechanisms leading to the changes in the makers should provide additional clues to the pathophysiology of this disease. For example, despite reporting raised levels of von Willebrand factor, soluble E selectin, and VCAM in a case-control study of 70 patients with type 2 diabetes, Steiner et al. (36) were unable to relate such increases to glycated hemoglobin or fructoasmine. However, they did correlate von Willebrand factor with hypertension and soluble E-selectin with low-density lipoprotein cholesterol.
In the current issue of The Journal of Clinical Endocrinology & Metabolism, Jilma et al. (37) have taken a further step in the search for the mechanism(s) behind these changes. Perhaps surprisingly, the continued infusion of insulin into healthy young men over a 24-h period resulted in no changes in sICAM, sVCAM, soluble E-selectin, von Willebrand factor or soluble thrombomodulin. Indeed, this is contrary to previous reports that insulin directly increases circulating adhesion molecules in diabetics and that high insulin levels do not induce endothelial function. However, although, in our view, correctly interpreting the study by Jilma et al. (37) as showing no short-term effect of insulin on the endothelium, it begs the question of whether or not this effect is present in patients with either form of diabetes and, if so, whether such an effect occurs over a longer period than that studied in this paper. Perhaps it is the degree of insulin resistance and ethnicity that may be the more important factors. For example, Chen et al. (38) studied the relationship between insulin resistance, soluble adhesion molecules E-selectin, sICAM, and sVCAM, and lipoprotein concentrations in 28 healthy, nondiabetic, and normotensive individuals and found that the degree of insulin resistance was significantly correlated with concentrations of the measured adhesion molecules, even after adjustment for differences in age, gender, body mass index, and all measures of lipoprotein concentrations. Thus, the relationships between soluble adhesion molecules in patients with hypertension, type 2 diabetes, and dyslipidemia may be due to the presence of insulin resistance in these clinical syndromes and raises the possibility that that insulin resistance may predispose individuals to coronary heart disease by activation of cellular adhesion molecules. Perhaps the latter may be one mechanism for the increase in coronary heart disease among the Indo-Asian population (and other ethnic groups, such as Pima Indians), who have a particularly high prevalence of insulin resistance (39).
When these questions are answered, we shall perhaps have a better understanding on the relationships between the metabolic changes in diabetes and their influence on the endothelium and whether or not this represents an additional therapeutic direction.
|
Acknowledgments |
|---|
Received February 2, 2000.
Accepted February 5, 2000.
|
References |
|---|
|
TopIntroductionReferences |
|---|
stimulates ICAM-1 expression in human vascular
smooth muscle cells. Arterioscler Thromb. 13:407–414.This article has been cited by other articles:
 |
|
 |
|
  F. M. Stewart, D. J. Freeman, J. E. Ramsay, I. A. Greer, M. Caslake, and W. R. Ferrell Longitudinal Assessment of Maternal Endothelial Function and Markers of Inflammation and Placental Function throughout Pregnancy in Lean and Obese Mothers J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 969 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Okapcova and D. Gabor The Levels of Soluble Adhesion Molecules in Diabetic and Nondiabetic Patients with Combined Hyperlipoproteinemia and the Effect of Ciprofibrate Therapy Angiology, November 1, 2004; 55(6): 629 - 639. [Abstract] [PDF]
|
|
|
|
|
|
J. Okapcova and D. Gabor The Levels of Soluble Adhesion Molecules in Diabetic and Nondiabetic Patients with Combined Hyperlipoproteinemia and the Effect of Ciprofibrate Therapy Angiology, November 1, 2004; 55(6): 629 - 639. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Sattar, J. Ramsay, L. Crawford, H. Cheyne, and I. A. Greer Classic and Novel Risk Factor Parameters in Women With a History of Preeclampsia Hypertension, July 1, 2003; 42(1): 39 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Glurich, S. Grossi, B. Albini, A. Ho, R. Shah, M. Zeid, H. Baumann, R. J. Genco, and E. De Nardin Systemic Inflammation in Cardiovascular and Periodontal Disease: Comparative Study Clin. Vaccine Immunol., March 1, 2002; 9(2): 425 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. André, D. Hartwell, I. Hrachovinová, S. Saffaripour, and D. D. Wagner Pro-coagulant state resulting from high levels of soluble P-selectin in blood PNAS, November 22, 2000; (2000) 250475997. [Abstract] [Full Text]
|
|
|
|
|
|
P. Andre, D. Hartwell, I. Hrachovinova, S. Saffaripour, and D. D. Wagner Pro-coagulant state resulting from high levels of soluble P-selectin in blood PNAS, December 5, 2000; 97(25): 13835 - 13840. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
