Relative survival potential of platelets is associated with platelet CXCR4/CXCR7 surface exposure and functional recovery following STEMI.

BACKGROUND AND AIMS: Platelets are critically involved in tissue repair and regeneration, which depend on their inflammatory properties and survival. SDF-1 ligates to CXCR4 and CXCR7 and contributes to the regulation of platelet survival. Platelet CXCR4/CXCR7 are involved in myocardial regeneration after infarction and are associated with outcomes in patients with symptomatic coronary artery disease. This study investigates the CXCR4/CXCR7 platelet survival axis ex vivo. METHODS: 87 patients with ST-segment elevation myocardial infarction (STEMI) were included and analyzed for platelet surface exposure of CXCR4, CXCR7, Annexin V binding and tetramethylrhodamine ethyl ester (TMRE) response. Serum of 38 patients was analyzed for FasL, TNFα, TNF RI, TNF RII and TRAIL with Bioplex®. The majority of patients received sequential cardiac MRI (intrahospital, 6-month follow-up). RESULTS: We found a strong and positive correlation between surface exposure of CXCR4 and CXCR7 (ρ = 0.856, p<0.001). Relative survival potential correlated significantly with both platelet surface exposure of CXCR4 and CXCR7 (ρ = 0.365, p = 0.019; ρ = 0.417, p = 0.006) and furthermore with improvement of myocardial left ventricular ejection fraction (LVEF) (ρ = 0.490, p = 0.013). High relative survival potential showed significantly higher levels for both CXCR4 and CXCR7 surface exposure (MFI 87.3 vs. 69.0, p = 0.037; MFI 71.4 vs. 59.3, p = 0.045). We found a significant change in absolute LVEF% over the course of 6 months in patients with high CXCR7 platelet surface exposure (LVEF% 44.3 vs. 60.0, p≤0.001). CONCLUSIONS: Platelet survival is associated with platelet surface exposure of CXCR4 and CXCR7 in STEMI patients and contributes to functional recovery after STEMI.

Evidence of an interaction between TGF-ß1 and the SDF-1/CXCR4/CXCR7 axis in human platelets.

BACKGROUND: TGF-ß1, SDF-1 and its cognate receptors CXCR4 and CXCR7 are expressed on the surface of human platelets and their expression levels are differently regulated in symptomatic coronary artery disease (CAD). All these proteins and receptors influence outcome in patients with symptomatic CAD. There might be a crosstalk between TGF-ß1 and the SDF-1/CXCR4/CXCR7 axis. Interrelations in CAD, especially in the context of platelets, are poorly understood. Therefore, we aimed to provide clinical and experimental evidence of interactions between TGF-ß1 and the SDF-1/CXCR4/CXCR7 axis in human platelets. METHODS AND RESULTS: Blood samples of the complete cohort (n=284) were analysed for platelet surface expression levels of TGF-ß1, SDF-1, CXCR4 and CXCR7 by flow cytometry. For stimulation assays platelet rich plasma was treated with TGF-ß1 or SDF-1 and then analysed by flow cytometry. Multiple regression analyses were run to show independent associations of TGF-ß1 with SDF-1, CXCR4, CXCR7 and clinical cofactors. Both, CXCR4 and CXCR7 significantly predicted TGF-ß1 (p<0.001 and p<0.001, respectively). After stimulation with SDF-1, surface expression of TGF-ß1 increased significantly when compared to resting platelets [mean TGF-ß1 MFI 19.01 vs. mean TGF-ß1 MFI 14.01, p<0.001]. Upon receptor blocking with either anti-CXCR4 or anti-CXCR7 monoclonal antibodies the enhancing effect of SDF-1 on TGF-ß1 surface expression was significantly blunted. Stimulation with TGF-ß1 did not alter SDF-1, CXCR4 or CXCR7 expression significantly. CONCLUSIONS: We provide first clinical and experimental data suggesting a cross-talk between TGF-ß and the SDF-1/CXCR4/CXCR7 axis in platelets which does not involve transcriptional modulation as shown previously for other cellular systems.