1. Fig. 5. Perturbations of AHR-STUB1-TF axis normalize the hyperthrombotic uremic phenotype without altering the bleeding risk.
Perturbations of AHR-STUB1-TF axis normalize the hyperthrombotic uremic phenotype without altering the bleeding risk. (A) The experimental design assessing the effect of YL-109 on the IS-specific uremic thrombosis model. A dose of heparin that increases activated partial thromboplastin time (aPTT) to the therapeutic range in mice (35) was administered 2 hours before the procedure. IP, intraperitoneal; PO, per os. (B) Representative traces of carotid artery blood flow showing TtO (arrow) in different groups. (C) An average TtO from each group of animals from three independent experiments is shown. The numbers of animals used include probenecid (n = 9), probenecid + IS (n = 12), probenecid + IS + YL-109 (n = 8), and probenecid + IS + heparin (n = 6). No difference in TtO was observed between probenecid and probenecid + IS + YL-109 (P = 0.65). Heparin significantly prolonged TtO compared to both IS and probenecid control groups (P = 0.021). Data are shown as means ± SD. (D) Mean normalized TF and STUB1 expression in the aortae of five mice injected with IS with or without YL-109 is shown. Student’s t test was performed. Data are shown as means ± SD. (E) Changes in TF expression in the individual aortae of IS + YL-109–treated animals and their respective TtO are shown. A Spearman correlation analysis was performed. (F) IS concentrations in the blood of mice exposed to 0.25% adenine diet for 2 weeks and animals on regular chow (control) (n = 5 per group). Data are shown as means ± SD. (G) An average TtO in control (regular diet) and adenine-induced CKD mice with AHR inhibitor (CH223191) or STUB1 enhancer (YL-109) (n = 5 per group) is shown. #P value compares the adenine and control groups. *P value compares CH and YL-109 groups with the adenine group. Data are shown as means ± SEM. (H) Average tail vein bleeding times for each group (n = 5 per group). Data are shown as means ± SD. (I) Differences in the average tail vein bleeding times (y axis) between probenecid control (non-CKD) and other groups (CKD). The solid line represents the average bleeding time of the control group, and the dotted lines represent two SDs of bleeding time from the control group. The shaded areas are the regions beyond 2 SD.
Moshe Shashar et al., Sci Transl Med 2017;9:eaam8475
Published by AAAS