Platelet and releasate lipidomics identify novel platelet activating mechanisms and ether-linked lysophosphatidylcholine and phosphatidylethanolamine 38:7 as predictors for platelet reactivity

Abstract

The activation of platelets and consequent thrombi formation are hallmark events for cardiovascular diseases. Both the secretion of lipid (in the platelet releasate) and intra-platelet lipid signaling have been shown to be important modulators to platelet activity and thrombosis. However, the relationship between platelet and releasate lipid profiles and how they respond to key agonists remain less clear. With a purposely designed human platelet targeted lipidomics platform which detected more than 550 platelet and releasate lipid species encompassing >30 lipid classes/subclasses, I presented in this study major changes to platelet lipidome triggered by acute and prolonged thrombin and collagen stimulations. I have demonstrated that overall lipid release from platelets was suppressed by collagen at the acute phase, a phenomenon that to my knowledge has yet to be reported. Additionally, prolonged thrombin treatment did not cause further production of lipid mediators. It nevertheless triggered an overall release of lipid into the surrounding (as releasate), including several proinflammatory and apoptotic lipids e.g., DG, ceramide, S1P, PA. Correlation tests between platelet/releasate lipid profiles and platelet surface markers P-selectin and PAC1 suggested that several di-/polyunsaturated phospholipid species and CoQ negatively correlated with collagen-stimulated PAC1 expression and PI 40:4(b) positively correlated with collagen-stimulated P-selectin expression. Finally, our study identified one lipid class, LPC-O, and one lipid species, PE 38:7, as potential predictors for the reactivity of platelet, with platelet LPC-O level positively correlated with collagen-stimulated increment of surface PAC1 expression and PE 38:7 correlated negatively with the increase in surface P-selectin in response to thrombin treatment.