Potential Therapeutic Targeting of Platelet-Mediated Cellular Interactions in Atherosclerosis and Inflammation

Abstract

Cellular interactions among platelets, leukocytes and endothelial cells are considered as a major cause of inflammation and atherosclerosis in many diseases. Via exposed surface receptors and released soluble substances, activated platelets play a crucial role in the initiation of inflammatory processes, resulting in endothelial injury and leading to formation of atherosclerotic plaque with possible thrombotic complications. Classic anti-platelet treatments (e.g. cyclooxygenase inhibitor or ADP-receptor antagonist) have favorable effects in patients with vascular diseases, but they also have several limitations such as increased bleeding risk or non-responsiveness. Thus, the need and opportunities for developing novel therapeutic inhibitors for platelet-mediated events are obvious. Animal and (pre)clinical human studies have suggested that some recently produced specific antagonists of P-selectin from α-granules, as well as its main ligand/receptor P-selectin Glycoprotein Ligand-1, the two major platelet chemokines CXCL4 and CCL5, as well as CD40L, may be considered potential new candidates in the treatment of atherogenesis and inflammation. In this review, we summarize the pathophysiological roles of these effectors in platelet activation and acute or chronic inflammation, and discuss the latest findings on promising antagonistic agents in basic and clinical studies in the prevention of platelet-mediated cellular interactions.

Circulating Endothelial Progenitor Cell and Platelet Microparticle Impact on Platelet Activation in Hypertension Associated with Hypercholesterolemia

“…IL-1β, CD40 ligand (CD40L), β-thromboglobulin] are implicated in the development of atherosclerosis [41], [42], [43]. Recently, animal and (pre)clinical human studies have suggested that the two major platelet chemokines PF4 and RANTES, as well as CD40L, may be considered potential new candidates in the treatment of atherogenesis and inflammation [44]. Likewise, the SDF-1α/CXCR4 axis has been shown to be implicated in the mobilization and EPC homing [45].…”

Is there a role for immune-to-brain communication in schizophrenia?

“…For example, selectin-mediated adhesion of leukocytes to the BBB endothelial cells is a key event that contributes to neuroinflammation by facilitating transmigration of inflammatory cells into the brain tissue. Animal and human healthy volunteer studies have identified promising new selectin inhibitors, which might be clinically useful to prevent acute and chronic inflammation; reviewed (Nagy et al 2012). Indeed, clinical trial of a selectin inhibitor has shown promising results in patients with asthma where it reduced airway recruitment of eosinophils (Romano 2005).…”

The Signaling Role of CD40 Ligand in Platelet Biology and in Platelet Component Transfusion

“…The CD40-CD40L system is associated with both pro-thrombotic and pro-inflammatory effects. Soluble CD40L contributes to the pathophysiology of atherosclerosis and atherothrombosis [ 52 ]. Because of its autocrine, paracrine, and endocrine activities, sCD40L enhances platelet activation, aggregation, and platelet-leukocyte conjugation that may lead to atherothrombosis [ 13 , 53 , 54 ].…”