Published online before print December 8, 2005, doi: 10.1161/01.RES.0000199295.14073.69
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Submitted on August 28, 2005
Revised on November 22, 2005
Accepted on November 29, 2005
Raised Plasma Soluble P-Selectin in Peripheral Arterial Occlusive Disease Enhances Leukocyte Adhesion
K. J. Woollard *;
From Alfred and Baker Medical Unit (K.J.W., A.M.D., J.C.-D.), Wynn Domain, Baker Heart Research Institute, Melbourne, Australia; Australian Centre for Blood Disease (S.K., S.J.), Monash University, Melbourne, Australia; F-Hoffman La Roche (D.K.), Basel, Switzerland.
* To whom correspondence should be addressed. E-mail: Kevin.Woollard{at}baker.edu.au.
Raised levels of soluble P-selectin (sP-selectin) have been reported in the plasma of patients with vascular diseases; however, the functional importance of this ligand remains unclear. In this study we have examined a potential role for plasma sP-selectin in regulating neutrophil adhesion in patients with peripheral arterial occlusive disease (PAOD). Patients with PAOD had significantly higher levels of sP-selectin (mean±SD: 73.3±13.0 versus 16.7±6.4 ng/mL) and enhanced whole blood leukocyte adhesion to platelets under shear. To examine whether the raised sP-selectin levels can directly influence leukocyte adhesion, isolated neutrophils were incubated with plasma from PAOD patients before and after immunodepletion of sP-selectin. Neutrophil adhesion to fibrinogen increased 2-fold following incubation with PAOD plasma, which was abrogated on sP-selectin immunodepletion. We subsequently demonstrated that recombinant sP-selectin dose-dependently (75 to 250 ng/mL) increased leukocyte adhesion to fibrinogen and platelet monolayers. This increase was PSGL-1 and Src kinase-dependent and correlated with an increase in sP-selectin-mediated Mac-1 activation. sP-selectin-stimulated neutrophil adhesion to platelet monolayers was inversely correlated with shear, such that at low shear (50 s-1) a 92.7%±15.7 increase in adhesion was observed decreasing to 38.5%±11.9 at 150 s-1 and 10.1%±7.4 at 300 s-1. These studies suggest a potentially important role for sP-selectin in modulating neutrophil adhesion in patients with PAOD, particularly at sites of low shear, where it raises the possibility that raised plasma sP-selectin levels may enhance leukocyte recruitment to vascular injury and promote disease progression.
Key words: atherosclerosis • cell adhesion molecules • leukocytes • peripheral vascular disease
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