Race differences in platelet reactivity: is protease activated receptor 4 a predictor of response to therapy?

Abstract

Several factors influence the incidence and severity of cardiovascular disease, such as environmental exposures, medical adherence, and genetic polymorphisms.1 One of the genetic components is a heritable interindividual variation in platelet reactivity, which is greater in black individuals than whites. This correlates strongly with the historical observations that black individuals develop cardiovascular disease at a younger age and have a higher incidence of mortality from the disease.2–4 Platelet RNA And eXpression study (PRAX-1) was designed to identify the specific genetic components that correlate with variations in platelet reactivity.5 This study recently identified an expression profile of mRNAs and microRNAs that are associated with race and protease activated receptor 4 (PAR4) reactivity. See accompanying article on page 2644 Thrombin is a potent platelet activator that initiates signaling in platelets and other cells via the G-protein coupled receptors called protease activated receptors (PARs); human platelets express PAR1 and PAR4.6 PARs are activated by proteolytic cleavage of the N-terminus to expose the tethered ligand, which interacts with the extracellular loops of the receptor. The primary determinant of PAR activation is the nature of the enzyme–substrate interaction, which determines the rate of proteolysis of the N-terminus. PAR1 is more efficiently cleaved by thrombin than PAR4. As a result, PAR4 is often thought of as a low-affinity backup receptor with redundant function because PAR1 and PAR4 initiate overlapping signaling cascades. Like many G-protein coupled receptors, PARs form homo- and hetero-oligomers (Figure).7 These lateral associations of PAR4 directly influence its activation and signaling.8–11 For example, interactions between PAR1 and PAR4 result in a 6- to 10-fold increase in the rate of PAR4 cleavage. …