The a-chemokine stromal derived factor 1 (SDF-1) plays an important role in maturation/platelet formation of megakaryocytes (Megs), and we recently reported that the responsiveness of hematopoietic cells to SDF-1 is optimal when its corresponding CXCR4 receptor is included into membrane lipid rafts (
). The formation of lipid rafts in vivo may be perturbed by cholesterol-lowering drugs, e.g., statins. Statins are effective in lowering LDL cholesterol and exert several pleiotropic effects on mature platelets, e.g., inhibit their activation. This latter effect is probably due to lowering of the cholesterol content in the membranes of mature platelets leading to the perturbation of membrane lipid raft formation which is required for proper platelet activation and signaling. However, under steady state conditions statins do not influence platelet production, no studies have been performed on their effects on platelet production in reactive thrombocytosis. In determining whether lipid raft formation plays a role in SDF-1- and stress-dependent thrombocytosis, we found that SDF-1 most efficiently stimulates in vitro platelet production when CXCR4 is included into membrane lipid rafts on Megs. At the molecular level, depletion of cholesterol from Megs membranes i) perturbed the responsiveness of megakaryocytic progenitors to an SDF-1 gradient, ii) inhibited SDF-1-mediated calcium flux and MAPKp42/44, AKT and STAT 1–6 phosphorylation in normal human Megs and (iii) inhibited F-actin polymerization, MMP-9 and VEGF secretion, and adhesion to endothelium and fibrinogen. More importantly we found that ex vivo-expanded human Megs, produced significantly fewer platelets during their transendothelial migration after preincubation with cholesterol-lowering MbCD. To evaluate whether cholesterol depletion from Megs affects platelet production we exposed C57Bl6 mice to statins (orally, 21 days, 750 mg/mouse) and observed that statins did not influence peripheral blood cell counts. However, when mice were acutely bled this treatment led to a significant amelioration of post-bleeding thrombocytosis as compared to untreated (control) mice. At the same time, recovery of erythrocyte and leukocyte counts was unaffected. Thus we demonstrated for the first time that statins affect CXCR4-mediated thrombopoiesis by perturbing lipid raft formation and should be considered as potential drugs to prevent post-trauma or post-operative thrombocytosis.
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