Clopidogrel effectively suppresses endothelial microparticle generation induced by indoxyl sulfate via inhibition of the p38 mitogen-activated protein kinase pathway

Background/Aims: Endothelial microparticles (EMPs) are closely associated with vascular dysfunction. We investigated the effects of several drugs on EMP generation in human umbilical vein endothelial cells (HUVECs), and the involvement of the mitogen-activated protein kinase (MAPK) in EMP generation. Methods: CD31+CD42-EMP counts were measured by flow cytometry in supernatants of HUVECs incubated with indoxyl sulfate. The EMP responses to losartan, lovastatin, clopidogrel, and mesoglycan were examined. We then measured the effects of MAPK inhibitors on EMPs. Results: (1) Indoxyl sulfate induced EMP release in HUVECs in a dose-dependent fashion; (2) all drugs (10-50 μM) inhibited EMP generation induced by indoxyl sulfate, with clopidogrel being the most effective; (3) the p38 MAPK inhibitor suppressed EMP generation induced by indoxyl sulfate, and (4) clopidogrel significantly suppressed MAPK signaling activated by indoxyl sulfate, with the most potency on p38. Conclusion: The p38 signaling involves EMP generation induced by indoxyl sulfate and is effectively suppressed by clopidogrel.