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(Circulation. 2000;102:e169.)
© 2000 American Heart Association, Inc.
Correspondence |
Heparin Also Interacts With Selectins and Modulates the Cell Adhesion Process
Department of Neurosurgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan, kyanaka@md.tsukuba.ac.jp
To the Editor:
We read with great interest the article by Peter and coworkers1 in the October 5, 1999 issue of Circulation in which the authors demonstrated the binding of heparin to integrin Mac-1 on stimulated leukocytes. Recent investigations have revealed that heparin can modulate biological processes, such as binding to adhesion receptors on endothelial cells and leukocytes.2 Leukocyte adhesion is a complex molecular process, and multiple adhesion receptor systems mediate the recruitment of leukocytes from the blood. The initial trafficking of circulating leukocytes to sites of inflammation is mediated by the selectin family of adhesion receptors; this is followed by the engagement of additional cellular recognition receptors, including the immunoglobulin superfamily and integrins. Heparin interacts with adhesion molecules, including integrin Mac-1 (CD11b/CD18) and selectins.3 4
Peter and colleagues speculated that the binding of heparin
to Mac-1 and the consequent inhibition of Mac-1 ligand binding could
directly modulate coagulation, inflammation, and cell proliferation.
They failed to mention the role of other adhesion molecules, such as
selectins, in this process. We would like to bring to the authors’
attention our study on the role of heparin in the cell adhesion
process.5 This study
revealed that heparin inhibits leukocyte adhesion by antagonizing the
function of selectins. We evaluated the efficacy of sulfated
polysaccharides (unfractionated heparin, low-molecular-weight heparin,
heparan sulfate, chondroitin sulfate, and dextran sulfate) on leukocyte
accumulation in the infarcted brain and found that the administration
of these sulfated polysaccharides led to reduced leukocyte
accumulation. The relative potency of leukocyte accumulation inhibition
of the sulfated polysaccharides tested was as follows: dextran sulfate
unfractionated heparin > low-molecular-weight heparin
chondroitin sulfate heparan sulfate. Potency was correlated with the
molecule’s degree of sulfation. We hypothesized that leukocyte
recruitment was due to an interaction between leukocyte selectins and
carbohydrate ligands, such as the sulfated polysaccharide side chains
of proteoglycans on the endothelial cell surface. Therefore, in
addition to integrin Mac-1, selectins also play an important role in
the cell adhesion process, and this promiscuous binding of heparin may
modulate inflammation and cell proliferation.
References
1.
Peter
K, Schwarz M, Conradt C, et al. Heparin inhibits ligand binding
to the leukocyte integrin Mac-1 (CD11b/CD18).
Circulation. 1999;100:1533–1539.
2.
Nelson
RM, Cecconi O, Roberts WG, et al. Heparin oligosaccharides bind L- and
P-selectin and inhibit acute inflammation. Blood. 1993;82:3253–3258.
3. Bârzu T, Van Rijn JL, Petitou M, et al. Endothelial binding sites for heparin: specificity and role in heparin neutralization. Biochem J. 1986;238:847–854.[Medline] [Order article via Infotrieve]
4.
Diamond
MS, Alon R, Parkos CA, et al. Heparin is an adhesive ligand for the
leukocyte integrin Mac-1 (CD11b/CD18). J Cell
Biol. 1995;130:1473–1482.
5. Yanaka K, Spellman SR, McCarthy JB, et al. Reduction of brain injury using heparin to inhibit leukocyte accumulation in a rat model of transient focal cerebral ischemia, I: protective mechanism. J Neurosurg. 1996;85:1102–1107.[Medline] [Order article via Infotrieve]
Response
Department of Internal Medicine III, University of Freiburg, Hugstetter Str 55, 79106 Freiburg, Germany, peter@med1.ukl.uni-freiburg.de
Departments of Internal Medicine III and Biometry, University of Heidelberg, Germany
We thank Yanaka et alR1 for their comments on the effects of heparin in cell adhesion processes. Indeed, because of space restrictions, we did not discuss the multiple functions of heparin in depth in our article.R2 We agree that the inhibition of P- and L-selectin by heparin may participate in the modulation of cell adhesion by heparin.
Only a few reports have addressed the inhibition of cell
adhesion by heparin. Most of these reports demonstrate an overall
inhibitory effect of heparin on leukocyte recruitment, without defining
the nature of the inhibition. For example, Yanaka et
alR1 demonstrated that
heparins inhibit leukocyte accumulation, reduce infarct size, and
improve outcome in cerebral ischemia in a rat model. At least 2 reports
define the inhibition of selectins as a potential mechanism by which
heparin modulates cell adhesion. In an original approach, Nelson et
alR3 demonstrated that
heparins directly inhibit L- and P-selectin; they further demonstrated
reduced neutrophil influx in an in vivo model of acute inflammation.
Koenig et alR4 proved
that L- and P-selectin were inhibited by heparins. For unfractionated
heparin, the IC (concentration that inhibits
50%) was 
10-fold less than the recommended levels for
anticoagulation in an in vitro binding assay that evaluated L- and
P-selectin–mediated cell adhesion.
Two major adhesion steps of the cascade of leukocyte adhesion, the initial rolling that is mediated by selectins and the buildup of a firm adhesion that is mediated by integrins such as Mac-1, can be inhibited by heparin. As shown by us for the inhibition of Mac-1,R2 the inhibition of L- and P-selectin is also achieved at heparin concentrations commonly used in the clinic. Thus, besides its anticoagulative properties, heparin may provide significant benefits by the blocking leukocyte adhesion and function in clinical settings such as cerebral and myocardial ischemia, restenosis after angioplasty, and thrombosis.
References
1. Yanaka K, Spellman SR, McCarthy JB, et al. Reduction of brain injury using heparin to inhibit leukocyte accumulation in a rat model of transient focal cerebral ischemia, II: dose-response effect and the therapeutic window. J Neurosurg. 1996;85:1108–1112.[Medline] [Order article via Infotrieve]
2. Peter K, Schwarz M, Conradt C, et al. Heparin inhibits ligand binding to the leukocyte integrin Mac-1 (CD11b/CD18). Circulation. 1999;100:1533–1539.
3. Nelson RM, Cecconi O, Roberts WG, et al. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood. 1993;82:3253–3258.
4. Koenig A, Norgard-Sumnicht K, Linhardt R, et al. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins: implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J Clin Invest. 1998;101:877–889.\.[Medline] [Order article via Infotrieve]
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