Abstract 300: Mesenchymal Stem Cells Attenuate High-Mobility Group Box 1 to Inhibit Aortic Aneurysms
Objective: Mesenchymal stem cells (MSCs) have been shown to attenuate aortic aneurysms (AAs) in animal models, but their precise mechanism of action remains undefined. In this study, we hypothesize that MSCs modulate NADPH oxidase activity in macrophages to mitigate high mobility group box 1 (HMGB1; a proinflammatory nuclear protein) secretion causing attenuation of vascular inflammation and AA formation.
Methods: Abdominal aortic tissue from male patients was obtained during open surgical repair and control aortic tissue was obtained from transplant donor patients. Human aortic tissue explants (or primary murine macrophages; 5x105 cells/well) were treated in vitro with elastase for 5 minutes, with or without co-culture with MSCs (1x105 cells per well) and supernatants were analyzed after 24hrs. In the murine in vivo model, AAs were induced in 8- to 12-week old C57BL/6 (WT) mice using an elastase-perfusion or heat inactivated elastase, with or without MSC treatment (given i.v. on day 1). Aortic tissue (harvested on day 14) or culture supernatants were analyzed for proinflammatory cytokine and HMGB1 production, as well as NADPH oxidase activity (measured by superoxide anion generation). Groups were compared using ANOVA followed by Bonferroni post hoc test.
Results: Aortic tissue from human AA patients had a significant increase in HMGB1 levels compared to control (50.7±4.8 vs. 26.8±2.5 ng/ml, respectively; n=9-11per group; mean +/- S.E.). HMGB1 production and NADPH oxidase activity in the elastase-treated human aortic tissue explants were significantly attenuated by co-culture with MSCs (63.7± 5.3 vs. 19.6±6.3 ng/ml and 1673±48 vs. 317± 89 Relative Light Units; respectively, n=5). In the murine AA model, HMGB1 expression in the aortic tissue from the elastase-perfused WT mice was significantly attenuated by MSC treatment (79.6±3.6 vs. 33.4±3.6 ng/ml). As compared to elastase-treated macrophages, the co-cultures of macrophages with MSCs significantly attenuated cytokine (IL-23, TNF-α and HMGB1) production as well as NADPH oxidase activity (1140±73 vs. 268±25 RLU).
Conclusions: HMGB1 production from macrophages plays an important role in AA formation and represents a novel target to protect against aneurysm formation by treatment with MSCs.
Author Disclosures: A.K. Sharma: None. G. Lu: None. M. Salmon: None. M. Murphy: None. G. Ailawadi: None. G.R. Upchurch Jr: None.
- © 2014 by American Heart Association, Inc.