Protease-Activated Receptor PAR-4: An Inducible Switch between Thrombosis and Vascular Inflammation?

Abstract

Thrombin triggers activation of platelets through protease-activated receptor 1 (PAR-1) and PAR-4. Both receptors are widely expressed and exert multiple platelet-independent functions. PAR signalling contributes to healing responses after injury, by promoting cytokine activity and cellular growth and mobility. Uncontrolled PAR activation, however, can prevent timely resolution of inflammation, enhance thrombogenic endothelial function and drive adverse remodelling. The specific role of PAR-4 in thromboinflammatory vascular disease has been largely underestimated, given the relatively limited expression of PAR-4 in non-platelet cells under healthy conditions. However, unlike PAR-1, PAR-4 expression adapts dynamically to numerous stimuli associated with thromboinflammation, including thrombin, angiotensin II, sphingosine-1-phosphate (S1P), high glucose and redox stress, suggesting expression is switched on ‘at need’. Prostacyclin negatively regulates PAR-4 expression at the post-transcriptional level, which may serve to fine-tune thrombin responses and limit these to the injury site. PAR-4 elicits inflammatory, mitogenic and proliferative actions not only in response to thrombin but also to numerous other inflammatory proteases, and can cross-talk with other receptor systems such as S1P and adenosine receptors. Accordingly, PAR-4 has emerged as a candidate player in vessel disease and cardiac post-infarction remodelling. Currently, PAR-4 is a particularly promising target for safer anti-thrombotic therapies. Recent studies with the PAR-4 antagonist BMS-986120 lend support to the concept that selective antagonism of PAR-4 may offer both an effective and safe anti-thrombotic therapy in the acute thrombotic setting as well as an anti-inflammatory strategy to prevent long-term progressive atherosclerotic disease in high-risk cardiovascular patients.