P-Selectin Antagonism in Inflammatory Disease

Objective We tested the hypothesis that endothelial proliferator-activated receptor-gamma (PPARγ) protects against vascular thrombosis using a transgenic mouse model expressing a PPARγ mutant (E-V290M) selectively in endothelium. Approach and Results The time to occlusive thrombosis of the carotid artery was significantly shortened in E-V290M mice compared with non-transgenic (non-Tg) littermates after either chemical injury with ferric chloride (5.1±0.2 vs. 10.1±3.3 minutes; P = 0.01) or photochemical injury with rose bengal (48±9 vs. 74±9 minutes; P = 0.04). Gene Set Enrichment Analysis demonstrated upregulation of NF-κB target genes, including P-selectin, in aortic endothelial cells from E-V290M mice (P < 0.001). Plasma P-selectin and carotid artery P-selectin mRNA were elevated in E-V290M mice (P < 0.05). P-selectin-dependent leukocyte rolling on mesenteric venules was increased in E-V290M mice compared with non-Tg mice (53±8 vs. 25±7 per minute; P = 0.02). The shortened time to arterial occlusion in E-V290M mice was reversed by administration of P-selectin blocking antibodies or neutrophil-depleting antibodies (P = 0.04 and P = 0.02, respectively) prior to photochemical injury. Conclusions Endothelial PPARγ protects against thrombosis through a mechanism that involves downregulation of P-selectin expression and diminished P-selectin-mediated leukocyte-endothelial interactions.

show abstract

“…Oral P-selectin blocking agents are being developed for several different clinical indications. 39-42 …”

Section: Discussionmentioning

confidence: 99%

Endothelial PPAR-γ Protects Against Vascular Thrombosis by Downregulating P-Selectin Expression

Jin

Gebska

Blokhin

et al. 2015

ATVB

View full text Add to dashboard Cite

show abstract

“…Antagonizing the chemokine receptor CCR2 via nanoparticle-mediated transfer of short interfering RNA decreases Ly6c high monocytes in peripheral tissues and reduces inflammation associated with atherosclerosis [75]. PSGL-1 (P-selectin glycoprotein ligand-1) on leucocytes interacts with E-and P-selectins on activated endothelium and platelets (P-selectin) [76]. PSGL-1 (P-selectin glycoprotein ligand-1) on leucocytes interacts with E-and P-selectins on activated endothelium and platelets (P-selectin) [76].…”

Section: Monocytes As a Drug Target In Atherosclerosismentioning

confidence: 99%

“…It is worth noting that Ly6c high monocytes express PSGL-1 at higher levels compared with Ly6c low monocytes, providing a hypothesis for specific accumulation in the growing lesion [34,41]. This complicates the idea of blocking either PSGL-1 or the membrane-bound receptor P-selectin [76]. This complicates the idea of blocking either PSGL-1 or the membrane-bound receptor P-selectin [76].…”

Section: Monocytes As a Drug Target In Atherosclerosismentioning

confidence: 99%

Immunological aspects of atherosclerosis

Woollard

2013

Clinical Science

View full text Add to dashboard Cite

Cardiovascular disease is the leading cause of death in several countries. The underlying process is atherosclerosis, a slowly progressing chronic disorder that can lead to intravascular thrombosis. There is overwhelming evidence for the underlying importance of our immune system in atherosclerosis. Monocytes, which comprise part of the innate immune system, can be recruited to inflamed endothelium and this recruitment has been shown to be proportional to the extent of atherosclerotic disease. Monocytes undergo migration into the vasculature, they differentiate into macrophage phenotypes, which are highly phagocytic and can scavenge modified lipids, leading to foam cell formation and development of the lipid-rich atheroma core. This increased influx leads to a highly inflammatory environment and along with other immune cells can increase the risk in the development of the unstable atherosclerotic plaque phenotype. The present review provides an overview and description of the immunological aspect of innate and adaptive immune cell subsets in atherosclerosis, by defining their interaction with the vascular environment, modified lipids and other cellular exchanges. There is a particular focus on monocytes and macrophages, but shorter descriptions of dendritic cells, lymphocyte populations, neutrophils, mast cells and platelets are also included.

show abstract

“…The role of P-selectins in these processes is yet to be determined, but P-selectin antagonists, as modulators of inflammation, have been proposed in vascular pathologies such as atherosclerosis. 111 Next to CAMs of the selectin family, integrins are also related to vascular processes. For instance, the increased expression of β3 integrin on endothelial cells is a welldescribed marker for ongoing angiogenesis.…”

Section: Role Of Cams In Vascular Changes Linked To Admentioning

confidence: 99%

Cell adhesion molecules in Alzheimer's disease

Wennström¹,

Nielsen²

2012

DNND

View full text Add to dashboard Cite

Cell adhesion molecules (CAMs) mediate interactions between cells and their surroundings that are vital to processes controlling for cell survival, activation, migration, and plasticity. However, increasing evidence suggests that CAMs also mediate mechanisms involved in several neurological diseases. This article reviews the current knowledge on the role of CAMs in amyloid-β (Aβ) metabolism, cell plasticity, neuroinflammation, and vascular changes, all of which are considered central to the pathogenesis and progression of Alzheimer's disease (AD). This paper also outlines the possible roles of CAMs in current and novel AD treatment strategies.

show abstract

P-Selectin Antagonism in Inflammatory Disease

Cited by 28 publications

References 71 publications

Endothelial PPAR-γ Protects Against Vascular Thrombosis by Downregulating P-Selectin Expression

Endothelial PPAR-γ Protects Against Vascular Thrombosis by Downregulating P-Selectin Expression

Immunological aspects of atherosclerosis

Cell adhesion molecules in Alzheimer's disease

Contact Info

Product

Resources

About