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Leukocyte-derived microparticles exaggerate endothelial senescence and vascular dysfunction induced by high glucose

Altamimy, R. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ; Qureshi, A.W. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ; Amoura, L. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ; El Habhab, A. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ; El Itawi, H. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ; Kassem, M. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ; Khemais, S. (CNRS, France ) ; Pollet, B. (CNRS, France ) ; El-Ghazouani, F. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ; Auger, C. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ; Schini-Kerth, V. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ; Toti, F. (INSERM, UMR 1260 nanomédecine régénérative, Strasbourg, France ) ;
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    Introduction Microparticles (MPs) are plasma membrane vesicles and vascular effectors. High levels of pro-inflammatory cytokines and procoagulant endothelial-derived MPs circulate in diabetic patients. We have shown that (i) leukocyte-derived MPs shed in response to stress are pro-inflammatory, procoagulant and prosenescent endothelial effectors; (ii) high glucose induces premature endothelial senescence. Objective To determine the possibility that leukocyte-derived MPs affect endothelial senescence and vascular function in response to high glucose. Methods Leukocyte MPs were isolated from rat splenocytes with either 5mg/ml LPS (MPLPS), 25ng/ml PMA/1mM A23187 ionophore (MPPMAi), or vehicle (MPCTL). Porcine coronary artery endothelial cells (ECs) at passage 1 were incubated for 48h with 1–30nM MPs in high or low glucose concentration (HG 25mM, NG 5.5mM). Senescence-associated β-galactosidase (SA-ß-GAL) activity was assessed by C12FDG, protein expression by Western blot analysis. Pig coronary artery rings were pre-incubated with HG or NG for 12h prior to addition of 1–30nM MPs for 12h. Bradykinin (BK)-induced endothelium-dependent relaxations were assessed in organ chambers, and staining of target proteins by confocal microscopy. Results At 10nM, MPLPS and MPPMAi enhanced SA-b-GAL activity both by about 2-fold in NG, and respectively 3 and 3.7-fold in HG. The expression of senescence markers p21, p16 doubled and that of eNOS decreased 2-fold. MPPMAi and MPLPS induced a concentration-dependent inhibition of BK-induced relaxation, inhibition by respectively 10nM and 30nM,being 65% in NG, amounting to about 85% in HG, whereas 30nM MPCTL had no effect. MPPMAi and MPLPS reduced eNOS expression by 60% in NG and 80% in HG. Conversely, VCAM-1, COX-2 were up-regulated. Conclusion Leukocyte-derived MPs enhance HG-induced alteration of the endothelial function by inducing premature senescence and might contribute to vascular dysfunction in diabetes patients.


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