Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote atherosclerosis

Abstract

Cerebrovascular and cardiovascular diseases are a major cause of morbidity and mortality. Soluble P-selectin (sP-selectin) is a biomarker for platelet/endothelial activation and is considered a risk factor for vascular disease. sP-selectin enhances procoagulant activity by inducing leukocyte-derived microparticle production and promotes activation of leukocyte integrins. However, it is not known whether it directly contributes to vascular complications. We investigated the effect of increased levels of sP-selectin on bloodbrain barrier (BBB) function, stroke outcome, and atherosclerosis by comparing wild-type mice with P-sel ⌬CT/⌬CT mice in which the endogenous P-selectin gene was replaced with a mutant that produces abnormally high plasma levels of sP-selectin. P-sel ⌬CT/⌬CT mice presented several abnormalities, including (1) higher BBB permeability, with 25% of the animals showing differential permeability between the right and left hemispheres;(2) altered social behavior with increased aggression; (3) larger infarcts in the middle cerebral artery occlusion ischemic stroke model; and (4) increased susceptibility to atherosclerotic, macrophage-rich lesion development in both male and female mice on the apoE ؊/؊ genetic background. Thus, elevated sP-selectin is not only a biomarker for vascular disease, but also may contribute directly to atherosclerosis and cerebrovascular complications. (Blood. 2009;113:6015-6022)

Soluble P-Selectin Levels Are Associated with Cardiovascular Mortality and Sudden Cardiac Death in Male Dialysis Patients

“…In mouse models of atherosclerosis, P-selectin gene knockout slowed development of atherosclerotic lesions [13,14], and overexpression led to increased plaque burden [15]. In humans, higher soluble P-selectin levels have been associated with greater atherosclerotic plaque burden [16,17] and myocardial infarction [18].…”

P-selectin promotes neutrophil extracellular trap formation in mice

“…Our data suggest that increased levels of sP-sel, seen in many chronic thrombotic and inflammatory conditions, may sensitize neutrophils for NETosis, which may further aggravate the pathology. Indeed, the increase in sP-sel in P-selectin DCT/DCT mice is associated with a procoagulant and proinflammatory phenotype 19,22 that results in larger thrombi in a deep vein thrombosis model, 20 more extensive infarcts in the middle cerebral artery ischemia/reperfusion stroke model, 19 and increased susceptibility to atherosclerosis on an ApoE 2/2 background. 19 We demonstrate in this study that sP-sel is also priming neutrophils for NETosis, a new mechanism likely contributing to the phenotype of the P-selectin DCT/DCT mice.…”

“…10 To evaluate NETosis, we first examined plasma DNA and nucleosome levels in these mice and found that they were similar to those of WT (DNA WT 5 92 6 10 ng/mL vs P-selectin DCT/DCT 5 84 6 2 ng/mL, P 5 .43; nucleosomes WT 5 0.05 6 0.01 vs P-selectin DCT/DCT 5 0.042 6 0.01 (absorbance 405nm, P 5 .68), indicating that at steady state, in either genotype, NETs do not appear to be spontaneously released into the circulation. However, knowing that the P-selectin DCT/DCT mice have a worse phenotype than WT mice in many pathological conditions known to produce NETs, 19,20 we wondered whether their neutrophils could be primed for NETosis. We isolated neutrophils from WT and P-selectin DCT/DCT mice and incubated them in the absence or presence of different stimulants for NETosis (Figure 2).…”

P-Selectin Antagonism in Inflammatory Disease

“…Evidence that sP-selectin has a direct role in atherosclerosis has been reported [33][34][35][36]. Studies from our laboratory demonstrated for the first time a functionally important role for sP-selectin in regulating leukocyte adhesion in patients with peripheral arterial occlusive disease [34].…”