Abstract 19216: IL-9 Promotes Mast Cell Activation and Endothelial Toxicity in Chronic Kidney Disease-Dependent Vein Graft Disease
Chronic kidney disease (CKD, with GFR < 60 ml/min/1.73 m2) independently predicts vascular events, including CABG vein graft failure. To elucidate mechanisms underlying this problem, we modeled CKD in C57BL/6 mice with 5/6ths nephrectomy, which reduces GFR by 60% vs control-GFR mice (1/3rd nephrectomy); we modeled vein grafting by IVC-to-carotid interposition grafting and harvested 4 wk post-op. We found that CKD augments vein graft neointimal hyperplasia (NH) 4-fold (p<0.001) and serum IL-9 levels 5-fold (p<0.001). We found that systemic anti-IL-9 IgG (compared with isotype control IgG, injected 3х/wk for 4 wk) reduced vein graft NH 4-fold in CKD mice (p<0.001). Because IL-9 is a critical mast cell (MC) growth factor, we tested the hypothesis that CKD-promoted vein graft NH involves MCs and toxicity to endothelial cells (ECs). In vein grafts from CKD compared with control mice, MC prevalence was 1.6±0.2-fold greater, assessed in cross sections stained with toluidine blue or with anti-tryptase or anti-chymase IgG (p<0.01); anti-IL-9 treatment normalized MC prevalence. Furthermore, the prevalence of activated (degranulating) MCs was 2.7±0.4-fold greater in vein grafts from CKD mice (23% vs 8%, p<0.01); anti-IL-9 treatment eliminated this difference, too. The extent of vein graft re-endothelialization was 50% less in CKD than in control mice (30% vs 60%, p<0.01), judged by anti-vWF IgG stain. However, anti-IL-9 IgG treatment augmented vein graft re-endothelialization by 45% (p<0.001). Mouse ECs in vitro proliferated 20-fold faster in 20% serum from control mice, compared with CKD mice (p<0.01). Anti-IL-9 IgG did not affect EC proliferation in control serum, but did augment EC proliferation in CKD serum 4.5-fold (compared with control IgG, p<0.05). To test if CKD-dependent vein graft NH can accelerate atherosclerosis (athero), we transplanted vein grafts from CKD and control mice into carotids of congenic, normal-GFR Apoe-/- mice; harvest was 4 wk later. In vein grafts from CKD mice, athero lesions were 2.4-fold larger and luminal area was 5-fold smaller (p<0.01). We conclude that CKD increases vein graft NH, and subsequent athero, through mechanisms involving IL-9-dependent increases in MC populations and MC activation, as well as EC toxicity.
Author Disclosures: L. Zhang: None. J. Wu: None. L. Brian: None. N.J. Freedman: None.
- © 2016 by American Heart Association, Inc.