Abstract 459: Myeloid-Derived Suppressor Cells (MDSCs) Prevent Cyclosporine A-Induced Vascular and Renal Endothelial Cell Injury
Cyclosporine A (CsA) is an immunosuppressive drug that can cause vascular and renal endothelial dysfunction and hypertension. Myeloid-derived suppressor cells (MDSCs) exert anti-inflammatory activity by inhibiting various innate and adaptive immune cells; however, the direct effects of CsA on MDSCs and whether MDSCs can prevent the detrimental CsA effects on endothelial cells are unknown. We hypothesized that CsA directly decreases MDSCs and that MDSCs prevent CsA-induced endothelial injury. CsA (50 uM) treatment of CD11b+/Gr-1+ MDSCs isolated from male C57BL6/J mice for 24 hours caused a dose-dependent decrease in MDSCs (Total CD11b+/Gr-1+ cell number: Veh=6,358,000, CsA 10 uM=3,505,000, CsA 25 uM=2,685,000, CsA 50 uM=1,425,000). Mouse cardiac vascular and glomerular endothelial cells were treated with CsA (50 uM) in the absence and presence of 75,000 isolated MDSCs for 24 hours. CsA significantly increased fibronectin and ICAM protein levels 1.5-2-fold in both vascular and glomerular endothelial cells compared to vehicle-treated endothelial cells. The presence of MDSCs prevented the CsA-induced increase in fibronectin and ICAM while having no effects in vehicle-treated endothelial cells. Additionally, CsA (50 uM) treatment of aortas isolated from male C57BL6/J mice for 24 hours markedly decreased maximal acetylcholine-induced relaxation responses and this was partially restored by co-incubation with MDSCs, and isolated kidneys treated with CsA had increased levels of fibronectin and this was ameliorated by co-incubation with MDSCs. In conclusion, CsA-induced decreases in MDSCs may play a role in endothelial cell injury and the augmentation of MDSCs may prevent the vascular and renal dysfunction and hypertension caused by CsA.
Author Disclosures: K.R. Bounds: None. V.L. Chiasson: None. M.H. Roman: None. B.M. Mitchell: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; NIH.
- © 2014 by American Heart Association, Inc.