Differences in Platelet LPA Responses in Healthy Donors and Coronary Artery Disease Patients

Abstract

Lysophosphatidic acid (LPA) stimulates platelet actin reorganization, adhesion, shape change, and aggregation and is thought to potentiate platelet responses following plaque rupture. We characterized the pharmacology of platelet responses to LPA [oleyl-LPA (18:1)] to provide insight into the known G-protein-coupled LPA receptors (LPA 1– 4) and observed donor-specific responses. 15 of 19 healthy donors displayed LPA-induced aggregation, but 4 donors (21%) consistently failed to aggregate to LPA. Among “LPA responsive” donors, alkyl-LPA (16:0) was more potent in stimulating platelet aggregation than LPA. The length of the acyl chain also influenced platelet responses with palmitoyl-LPA (16:0) ~ oleoyl-LPA (18:1) > myristoyl-LPA (14:0) and stearoyl-LPA (18:0) > hexanoyl-LPA (6:0). Preincubation of washed platelets with the LPA1/3 antagonist VPC32179 or VPC12249 reduced both LPA- and alkyl-LPA (16:0)-induced aggregation and Rho activation. LPA had no effect on VASP-P in LPA responsive donors. In all 4 “unresponsive” donors, LPA enhanced PGI2-induced VASP-P by an average of 17%, suggesting the presence of additional inhibitory pathways. We also measured LPA-induced aggregation in patients with stable coronary artery disease and found a non-response rate of 1.4%. It remains to be established whether the lower non-response rate to LPA in coronary artery disease patients relates to the development of vascular disease. Support: NIH R01HL078663