Abstract 16658: Pannexin-1 Channels on Endothelial Cells Modulates Aortic Aneurysm Formation
Objective: The pathogenesis of aortic aneurysm (AA) formation involves vascular remodeling and inflammation. Pannexin-1 (Panx1) channels are expressed on endothelial cells and modulate cellular ATP release. This study investigates the role of Panx1 in the pathogenesis of AA formation.
Methods: Abdominal AAs were induced in 8- to 12-week old male C57BL/6 (WT), VECadCreERT2+/Panx1fl/fl (endothelial cell-specific Panx1 inducible knockout (KO) and SMMHC-CreERT2+/Panx1fl/fl (smooth muscle cell-specific Panx1 inducible KO) mice using topical (0.4 U/mL type 1 porcine pancreatic elastase) treatment or saline as control. On day 14, the abdominal aorta was measured by video micrometry and expressed as percentage increase over baseline. Cytokine expression in aortic tissue was analyzed by ELISA. Immunohistochemistry was performed to analyze inflammatory cell infiltration and elastic fiber disruption. Elastase or cytomix (IL-17+HMGB1+IL-1β; 10ng/ml each) exposure-induced ATP release or leukocyte transmigration was measured using human aortic endothelial cells (HAECs) with/without carbenoxolone (50μM; a Panx1 inhibitor) treatment. Groups were compared using ANOVA followed by Tukey’s test.
Results: Aortic diameter was significantly increased in elastase-treated WT mice compared to controls (114±2.7% vs 8.9±2.3%; mean +/- S.E.; n=5/group, p<0.001). Elastase-treated endothelial-specific Panx1 KO mice (n=7), but not the smooth muscle-specific Panx1 KO mice (n=10), had a significant attenuation in abdominal AA formation compared to elastase-treated WT mice (72±5.4%* and 100±6.0% vs. 114±2.7%, respectively; *p<0.001). A significant mitigation of pro-inflammatory cytokines (IL-17, HMGB1, MCP1, TNF-α, KC), cell infiltration (CD3+ T cells, macrophages and neutrophils) and decrease in elastic fiber disruption occurred in aortic tissue from elastase-treated endothelial-specific Panx1 knockout mice compared to elastase-treated WT mice. Carbenoxolone treatment of HAECs significantly attenuated ATP release and neutrophil transmigration induced by elastase or cytomix.
Conclusions: Panx1 channels on endothelial cells modulate inflammation, leukocyte trafficking and AA formation which is likely mediated via ATP release.
Author Disclosures: A.K. Sharma: None. M. Spinosa: None. M.D. Salmon: None. G. Su: None. A.K. Narahari: None. B.E. Isakson: None. K.S. Ravichandran: None. G.R. Upchurch: None.
- © 2016 by American Heart Association, Inc.