Cell Adhesion Molecules in Cardiovascular Disease and Its Risk FactorsWhat Can Soluble Levels Tell Us?
Andrew D. Blann and
Gregory Y. H. Lip
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
|
---|
There are at least three reasons why considerable
research energy is currently being directed toward the study of cell
adhesion molecules. The blockade of the interaction between leukocytes
and the endothelium by agents that mimic or inhibit these adhesion
molecules may become a new class of therapeutic agents (1, 2, 3), study of
the expression of the molecules on the surface of various cells or of
the soluble form in the plasma may provide insights into their role(s)
in pathophysiology (4, 5), and levels of soluble cell adhesion
molecules in the plasma may be useful tools in stratifying disease
severity or prognosis (6, 7).
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
|
---|
We acknowledge the support of the City Hospital NHS Trust
Research and Development Programme for support of the Haemostasis,
Thrombosis and Vascular Biology Unit.
Received February 2, 2000.
Accepted February 5, 2000.
 |
References
|
---|
-
Hayward R, Campbell B, Shin YK, Scalia R, Lefer
AM. 1999 Recombinant soluble P-selectin ligand-1 protects against
myocardial ischemic reperfusion in cats. Cardiovasc Res. 41:6576.[CrossRef][Medline]
-
Zhang RL, Chopp M, Jiang N, et al. 1995 Anti-intercellular adhesion molecule-1 antibody reduces ischaemic cell
damage after transient but not permanent middle cerebral artery
occlusion in the Wistar rat. Stroke. 26:14381443.[Abstract/Free Full Text]
-
Tsukamoto K, Yokono K, Amano K, et al. 1995 Administration of monoclonal antibodies against vascular cell adhesion
molecule-1/very late antigen-4 abrogates predisposing autoimmune
diabetes in NOD mice. Cell Immunol. 165:193201.[CrossRef][Medline]
-
Tanio JW, Chandrasekar BB, Albelda SM, Eisen HJ. 1994 Differential expression of the cell adhesion molecules ICAM-1,
VCAM-1 and E-selectin in normal and post-transplantation myocardium. Circulation. 89:17601768.[Abstract]
-
Kuzu I, Bicknell R, Fletcher CDM, Gatter KC. 1993 Expression of adhesion molecules on the endothelium of normal tissue
vessels and vascular tumours. Lab Invest. 69:322328.[Medline]
-
Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer
MJ, Allen J. 1998 Plasma concentrations of soluble intercellular
adhesion molecule-1 and risks of future myocardial infarction in
apparently healthy men. Lancet. 351:8892.[CrossRef][Medline]
-
Blann AD, Seigneur M, Steiner M, Miller JP, McCollum
CN. 1998 Circulating ICAM-1 and VCAM-1 in peripheral artery
disease and hypercholesterolaemia: relationship to the location of
atherosclerotic disease, smoking, and in the prediction of adverse
events. Thromb Haemost. 79:10801085.[Medline]
-
Schleiffenbaum B, Spertinin O, Tedder TF. 1992 Soluble L-selectin is present in human plasma at high levels and
retains functional activity. J Cell Biol. 11:229238.
-
Gamble JR, Skinner MP, Berndt MC, Vadas MA. 1990 Prevention of activated neutrophil adhesion to endothelium by soluble
adhesion protein GMP 140. Science. 249:414417.[Medline]
-
Fijnheer R, Frijns CJM, Korteweg J, et al. 1997 The
origin of P-selectin as a circulating plasma protein. Thromb Haemost. 77:10811085.[Medline]
-
Blann AD, Lip GYH. 1997 Hypothesis: is soluble
P-selectin a new marker of platelet activation? Atherosclerosis. 128:135138.[CrossRef][Medline]
-
Chong BH, Murray B, Berndt MC, Dunlop LC, Brighton T,
Chesterman CN. 1994 Plasma P-selectin is increased in thrombotic
consumptive disorders. Blood. 83:15351541.[Abstract/Free Full Text]
-
Jilma B, Fasching P, Ruthner C, et al. 1996 Elevated circulating P-selectin in insulin dependent diabetes mellitus. Thromb Haemost. 76:328332.[Medline]
-
Blann AD, Faragher EB, McCollum CN. 1997 Increased
soluble P-selectin in ischaemic heart disease: a new marker for the
progression of atherosclerosis. Blood Coag Fibrinolysis. 8:383390.[Medline]
-
Pigott R, Dillon LP, Hemingway IH, Gearing AJ. 1992 Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the
supernatants of cytokine activated cultured endothelial cells. Biochem
Biophys Res Commun. 187:584589.[Medline]
-
Miwa K, Igawa A, Inoue H. 1997 Soluble E-selectin,
ICAM-1 and VCAM-1 in systemic and coronary circulation in patients with
variant angina. Cardiovasc Res. 36:3744.[CrossRef][Medline]
-
Blann AD, Amiral J, McCollum CN. 1996 Soluble
endothelial cell markers and adhesion molecules in ischaemic heart
disease. Br J Haematol. 95:263265.[Medline]
-
Blann AD, Amiral J, McCollum CN. 1997 Increased
soluble thrombomodulin and soluble E-selectin as predictors of disease
following myocardial infarction. Eur J Haematol. 58:115120.
-
Belch JJF, Shaw JW, Kirk G, et al. 1997 The white
blood cell adhesion molecule E-selectin predicts restenosis in patients
with intermittent claudication undergoing precutaneous transluminal
angioplasty. Circulation. 95:20272031.[Abstract/Free Full Text]
-
Blann AD, Morris J, McCollum CN. 1996 Soluble
L-selectin in atherosclerosis: relationship to soluble E-selectin and
soluble P-selectin. Atherosclerosis. 126:227231.[CrossRef][Medline]
-
Siminiak T, Smielecki J, Dye JF, et al. 1996 Detection of soluble adhesion molecules VCAM-1 and L-selectin during
myocardial infarction. Eur Heart J. 17 (Abstract
Supplement):353.
-
Haught WH, Mansour M, Rothlein R, et al. 1996 Alterations in circulating intercellular adhesion molecule-1 and
L-selectin: further evidence for chronic inflammation in ischaemic
heart disease. Am Heart J. 132:18.[Medline]
-
Blann AD, McCollum CN. 1994 Increased levels of
soluble adhesion molecules in atherosclerosis. Thromb Haemost. 72:151154.[Medline]
-
Peter K, Nawroth P, Conradt C, et al. 1997 Circulating vascular cell adhesion molecule-1 correlates with the
extent of human atherosclerosis in contrast to circulating ICAM-1,
E-selectin, P-selectin and thrombomodulin. Arterioscler Thromb Vasc
Biol. 17:505512.[Abstract/Free Full Text]
-
De Caterina R, Basta G, Lazzerini G, et al. 1997 Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of
atherosclerosis. Arterioscl Thromob Vasc Biol. 17:26462654.[Abstract/Free Full Text]
-
Blann AD, Wadley M, Dobrotova M, Jayson MI, Sanders P,
McCollum CN. 1998 Soluble PECAM in cancer, atherosclerosis and in
connective tissue diseases. Blood Coag Fibrinolysis. 9:99103.[Medline]
-
Ross R. 1993 The pathogenesis of atherosclerosis: a
perspective for the 1990s. Nature 362:801809.
-
Blann AD. 1999 Endothelial cell damage and the
development or progression of atherosclerosis. Clin Sci97
:119121.
-
Thompson SG, Kienast J, Pyke SDM, et al. for the
ECAT Group. 1995 Hemostatic factors and the risk of myocardial
infarction or sudden death in patients with angina pectoris. N
Engl J Med. 332;635641.
-
Braun M, Pietsch P, Schror K, Baumann G, Felix SB. 1999 Cellular adhesion molecules on vascular smooth muscle cells. Cardiovasc Res. 41:395341.[CrossRef][Medline]
-
Wittig BM, Treichel U, Blaheta R, et al. 1997 Soluble E-selectin enhances intercellular adhesion molecule-1 (ICAM-1)
expression in human tumour cell lines. Exp Cell Res. 237:364370.[CrossRef][Medline]
-
Couffinhal T, Duplaa C, Labat L, et al. 1993 Tumour
necrosis factor-
stimulates ICAM-1 expression in human vascular
smooth muscle cells. Arterioscler Thromb. 13:407414.[Abstract]
-
Carter AM, Grant PJ. 1997 Vascular homeostasis,
adhesions molecules, and macrovascular disease in non-insulin dependent
diabetes mellitus. Diabetic Med. 14:423432.[CrossRef][Medline]
-
Blann AD, Lip GYH. 1998 Endothelial integrity,
soluble adhesion molecules and platelets markers in type 1 diabetes
mellitus. Diabetic Med. 15:634642.[CrossRef][Medline]
-
Stehouwer CDA, Lambert J, Donker AJM, van Hinsburgh
VWM. 1997 Endothelial dysfunction and pathogenesis of diabetic
angiopathy. Cardiovasc Res. 34:5568.[CrossRef][Medline]
-
Steiner M, Reinhardt KM, Krammer B, Ernst B, Blann
AD. 1994 Increased levels of soluble adhesion molecules in type 2
(non-insulin dependent) diabetes mellitus are independent of glycaemic
controls. Thromb Haemost. 72:979984.[Medline]
-
Jilma B, Dallinger S, Hergovich N, Eichler HG, Richter
V, Wagner OF. 2000 Effects of hyperinsulinaemia on plasma levels
of circulating adhesion molecules. J Clin Endocrinol Metab. 85:17481751.[Abstract/Free Full Text]
-
Chen NG, Holmes M, Reaven GM. 1999 Relationship
between insulin resistance, soluble adhesion molecules, and mononuclear
cell binding in healthy volunteers. J Clin Endocrinol Metab. 84:34853489.[Abstract/Free Full Text]
-
Williams B. 1995 Westernised Asians and
cardiovascular disease: nature or nuture? Lancet. 345:401402.[CrossRef][Medline]