Altered platelet lipidomic profile influences thrombotic disposition: modulation by the CXCL12-CXCR4-CXCR7 Axis

M. Chatterjee, D. Rath, J. Schlotterbeck, J. Rheinlaender, B. Walker-Allgaier, T. E. Schäffer, M. Lämmerhofer, M. Gawaz (1Tübingen, Germany)

Vascular Wall, Platelets and Acquired Problems
Date: 16.02.2017,
Time: 14:00 - 15:15

Objective: CXCR7 agonist ameliorates atherosclerosis in Apoe-/- mice. Since CXCR7 surface expression on platelets and plasma CXCL12 levels are enhanced in acute coronary syndrome (ACS), both with significant prognostic impact, this study explores the atherothrombotic influence of CXCL12-CXCR4/CXCR7 axis on platelet lipid associations and characterizes the platelet lipidome in coronary artery disease (CAD) patients.

Methods: Flow cytometry, immunofluorescence confocal microscopy, impedance aggregometry, untargeted lipidomics analysis (UHPLC-ESI-QTOF-MS/MS), live imaging of single platelets by scanning ion conductance microscopy, calibrated automated thrombinoscopy, ex vivo flow chamber assay, in vivo occlusive thrombosis model.

Results: LDL/oxLDL enhanced reactive oxygen species (ROS), mitochondrial superoxide generation, whereby platelets serve as intracellular compartment for (per)oxidative lipid modification, counteracted by SOD2-mimetic MnTMPyP. Lipidomics revealed enhanced intraplatelet oxidized phospholipids, cholesteryl esters, sphingomyelin, lysoPC, di-,mono-acyglycerols, decreased ceramides levels in CAD patients suggesting a dynamic interaction between plasma and platelet lipids. Enhanced platelet-oxLDL in CAD patients, correlated with platelet CXCR7 surface expression, plasma tryglycerides, HDL, while inversely with CXCR4, plasma LDL. Platelet-oxLDL was elevated in ACS patients with angiographic evidence of intracoronary thrombi. Ex vivo analysis of intracoronary thrombi sections revealed oxLDL deposition in platelet-enriched areas. LDL/oxLDL induced degranulation, αIIbβ3-integrin activation, aggregation, apoptosis, thrombin generation and dynamic shape change. Further, LDL/oxLDL enhanced thrombus formation ex vivo and in vivo in mice (FeCl3 induced carotid injury). LDL-oxLDL enhanced platelet CXCL12 release, differentially regulated CXCR4-CXCR7 surface exposure decreasing CXCR4 while enhancing CXCR7 expression. CXCL12-CXCR4-CXCR7 prompted LDL/oxLDL uptake by upregulating surface availability of the scavenger receptors CXCL16-SR/PS-OX and ApoER2, also synergistically augmented the LDL/oxLDL-induced pro-oxidative and thrombogenic platelet functions.

Conclusion: Pro-oxidative platelet lipidome might propagate thrombotic disposition, a mechanism potentially modulated by CXCL12-CXCR4-CXCR7 axis to influence disease progression and prognosis in CAD.