Abstract 15118: Saxagliptin Reduces Lesion Formation and Reverses Endothelial Dysfunction in CETP-ApoB100 Mice With Atherosclerosis
Background: Endothelial cell (EC) dysfunction during atherogenesis is evidenced by reduced nitric oxide (NO) bioavailability and increased nitroxidative (ONOO-) stress. We hypothesized that saxagliptin, a DPP4 inhibitor, would reverse EC dysfunction and reduce atheroma development by enhancing endothelial NO synthase (eNOS) activity. To test this hypothesis, we measured the effects of saxagliptin on EC function in CETP-ApoB100 transgenic mice maintained on a high-fat diet. Changes in NO and ONOO- release were correlated with atherosclerotic lesion development, glucose control, and eNOS expression.
Methods: CETP-ApoB100 transgenic mice were treated with vehicle (animals exposed to low-fat and high-fat diets) or saxagliptin (10 mg/kg/day) for 26 weeks. NO and ONOO- release from aortic and glomerular ECs was measured ex vivo using amperometric nanosensors and correlated with fasting and postprandial glucose levels. eNOS expression was measured by real-time PCR (qPCR). The development of atherosclerotic lesions was evaluated by en face Oil Red O staining of aortic sections isolated from representative animals.
Results: As compared to the low-fat diet, the administration of a high-fat diet for 26 weeks resulted in a 50% reduction in aortic and glomerular NO/ONOO- ratio, an indicator of eNOS uncoupling. Animals fed a high-fat diet were also found to have an increased number of aortic surface atherosclerotic lesions as compared to animals in the low-fat control group (p<0.05). Saxagliptin treatment increased the maximal release of NO in aortic ECs by 18% (203 ± 16 nM to 239 ± 14 nM) and the overall NO/ONOO- ratio by 25% (p<0.01), due to a concomitant reduction in ONOO- levels. Similar changes were observed in glomerular ECs following saxagliptin treatment. Saxagliptin also reduced aortic lesion areas by more than 50%. The effects of saxagliptin on NO release and lesion development were not associated with changes in eNOS expression or postprandial glucose levels.
Conclusion: Saxagliptin treatment reversed endothelial dysfunction and reduced atherosclerotic lesion area in a transgenic mouse model of human atherosclerosis. These findings provide new insights into the potential atheroprotective effects of saxagliptin beyond glucose control.
- © 2013 by American Heart Association, Inc.