Abstract 15154: Aleglitazar, a Dual PPARa/? Agonist, Enhances Nitric Oxide Release and Reduces Nitroxidative Stress in Obese Zucker Rats: Comparison to Rosiglitazone and Fenofibrate
Background: Endothelial cell (EC) dysfunction contributes to insulin resistance in diabetes and is characterized by reduced nitric oxide (NO) release and increased nitroxidative stress. The purpose of this study was to test the effect of aleglitazar, a dual PPARα and PPARγ agonist, on EC function in obese Zucker rats. The effects of aleglitazar on NO and peroxynitrite (ONOO-) release were measured in glomerular ECs and correlated with eNOS expression. Treatment effects with aleglitazar were compared to the PPARα agonist, fenofibrate, the PPARγ agonist, rosiglitazone, and an NAD(P)H oxidase inhibitor.
Methods: Zucker obese rats were assigned to one of four treatment groups: (1) vehicle (sterile saline solution); (2) aleglitazar at 0.3 mg/kg/day; (3) fenofibrate at 50 mg/kg/day; and (4) rosiglitazone at 10 mg/kg/day. Each treatment was administered by gavage over a period of nine weeks. NO and ONOO- release from glomerular ECs was measured ex vivo using amperometric nanosensors. EC function was correlated with changes in eNOS expression, body weight, fasting glucose (FG), and postprandial glucose levels. As an additional control, we also tested the effects of the NAD(P)H oxidase inhibitor, S17834 (40 μM), in isolated tissue.
Results: Aleglitazar treatment increased NO release by 25% (p<0.001) in glomerular ECs with concomitant reductions in ONOO- levels as compared to vehicle treatment. The NO/ONOO- ratio, an indicator of NO synthase uncoupling, increased by 33% with aleglitazar treatment. Aleglitazar also increased eNOS expression by 80% (p<0.001) and reduced FG levels by 21% (p<0.001) as well as postprandial glucose levels. Rosiglitazone also improved the NO/ONOO- ratio in ECs by 34% and reduced FG levels. No significant improvements in EC function were observed with fenofibrate treatment. Treatment ex vivo with S17834 increased NO release by 19% and reduced ONOO- production similar to PPARγ agonists.
Conclusion: Aleglitazar and rosiglitazone, but not fenofibrate, were observed to reverse EC dysfunction in obese rats by enhancing eNOS function and expression while reducing oxidase activity. These results indicate that agents with PPARγ agonist activity improve EC function in this animal model of diabetes.
- © 2013 by American Heart Association, Inc.