Abstract 062: Up-regulation Of Adenosine A2a Receptor Contributes To Epoxyeicosatrienoic Acids-induced Improvement In Endothelial Function And Decreases In Renal Inflammation In Obese Mice
Epoxyeicosatrienoic acids (EETs) and adenosine activation of A2A receptor have anti-inflammatory properties and play a role in the regulation of vascular tone. During salt loading, renal response to A2A receptor activation is exacerbated via increased EETs production. However, potential EETs activation of adenosine signaling remains elusive. We hypothesize that increased EETs levels, via inhibition of soluble epoxide hydrolase, (sEH), improve endothelial function in type 2 diabetes through the up-regulation of A2A receptor to increase NO production. Obese db/db mice were treated with the sEH inhibitor t-AUCB (10 mg/L) alone or plus the A2A receptor antagonist SCH58261 (10 mg/kg, biweekly) for 12 weeks. Inhibition of sEH up-regulated renal A2A receptor expression and improved aortic ring relaxation to acetylcholine in obese db/db mice compared to lean (p<0.05). Administration of t-AUCB also reduced renal T-cell infiltration and apoptosis and increased renal eNOS expression in db/db mice. Co-administration of SCH58261 with t-AUCB reduced t-AUCB’s ability to improve aortic ring relaxation to acetylcholine, decreased renal eNOS expression and increased renal T-cell infiltration and apoptosis in db/db mice. Inhibition of sEH also restored the decrease in renal nitrate/nitrite and cGMP levels in db/db mice (renal nitrate/nitrite was 6.7±1 in db/db plus t-AUCB vs. 3.6± 0.7 nmol/mg in db/db and renal cGMP was 3.5± 0.4 in db/db plus t-AUCB vs. 2 ± 0.2 pmol/mg in db/db, p<0.05) and these changes were decreased by co-administration of SCH58261. To further explore the role of A2A receptor in EETs-induced improvement in endothelial function and decreases in renal inflammation, wild type control (WT) and A2A knock-out (KO) mice were fed high fat diet (HF) for 12 weeks with or without t-AUCB treatment. A2A KO mice fed HF displayed lesser aortic endothelial relaxation to acetylcholine and a decrease in renal eNOS expression compared to HF fed WT mice and inhibition of sEH improved aortic ring relaxation to acetylcholine in WT but not in A2A KO mice fed HF. These data suggest that EETs up-regulation of A2A receptor improves endothelial function and decreases inflammation via eNOS-dependent activation of NO production.
Author Disclosures: A.A. Elmarakby: None. C. Pye: None. B. Baban: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2014 by American Heart Association, Inc.