Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 53, Issue 4, Pages 730-741Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2012.05.045
Keywords
PPAR beta/delta; Diabetic rat; Endothelial dysfunction; NADPH oxidase
Funding
- Comision Interministerial de Ciencia y Tecnologia [SAF2011-28150, SAF2010-22066-C02-01, SAF2010-22066-C02-02]
- Ministerio de Ciencia e Innovacion, Instituto de Salud Carlos III (Red HERACLES), Spain [RD06/0009]
- Spanish Ministry of Science and Education
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Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. Herein, we have analyzed if the peroxisome proliferator-activated receptor-beta/-delta (PPAR beta/delta) agonist GW0742 exerts protective effects on endothelial function in type 1 diabetic rats. The rats were divided into 4 groups: control, control-treated (GW0742, 5 mg kg(-1) day(-1) for 5 weeks), diabetic (streptozotocin injection), and diabetic-treated. GW0742 administration in diabetic rats did not alter plasma glucose, systolic blood pressure, or heart rate, but reduced plasma triglyceride levels. The vasodilatation induced by acetylcholine was decreased in aortas from diabetic rats. GW0742 restored endothelial function, increasing eNOS phosphorylation. Superoxide production, NADPH oxidase activity, and mRNA expression of prepro endothelin-1, p22(phox), p47(phox), and NOX-1 were significantly higher in diabetic aortas, and GW0742 treatment prevented these changes. In addition, GW0742 prevented the endothelial dysfunction and the upregulation of prepro endothelin-1 and p47(phox) after the in vitro incubation of aortic rings with high glucose and these effects were prevented by the PPAR beta/delta antagonist GSK0660. PPAR beta/delta activation restores endothelial function in type 1 diabetic rats. This effect seems to be related to an increase in nitric oxide bioavailability as a result of reduced NADPH oxidase-driven superoxide production and downregulation of prepro endothelin-1. (c) 2012 Elsevier Inc. All rights reserved.
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