Therapeutic Targeting of P-Selectin in Atherosclerosis

Abstract

P-selectin is an inflammatory adhesion molecule expressed on activated platelets and endothelial cells. The role of inflammatory cells and adhesion molecules in the development and progression of vascular diseases has been well studied in the past two decades and it is now recognised that many of the cellular and molecular events that underlie atherosclerotic vascular disease are inflammatory in nature. The critical role of P-selectin in both leukocyte recruitment and vascular disease progression has been confirmed in knockout animal models, where P-selectin knockout mice crossed with apoE deficient mice exhibit significantly reduced atherosclerosis and leukocyte recruitment in the plaque. Being the primary adhesion molecule in initiating cell activation and cell adhesion to platelets and endothelial cells, P-selectin is therefore an attractive therapeutic target in vascular disease. However the basic tenet of targeting P-selectin may be complicated by the presence of a soluble form of P-selectin (sP-selectin). sP-selectin, lacking the cytosolic/transmembrane domain, has been identified circulating in plasma and is thought to either be derived from the secretion of an alternatively spliced protein that lacks the transmembrane domain and/or from proteolytic cleavage of the membrane form, thus reflecting the activated state of both platelets and/or endothelial cells. This review will discuss the role of P-selectin in inflammatory disease particularly in atherosclerosis and will highlight current in vitro and in vivo discoveries.