Activation of peroxisome proliferator-activated receptor-β/-δ (PPARβ/δ) prevents endothelial dysfunction in type 1 diabetic rats.
Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. Herein, we have analyzed if the peroxisome proliferator-activated receptor-β/-δ (PPARβ/δ) 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 PPARβ/δ antagonist GSK0660. PPARβ/δ 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.
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
Ana María
AM
Quintela
Rosario
R
Jiménez
Manuel
M
Gómez-Guzmán
María José
MJ
Zarzuelo
Pilar
P
Galindo
Manuel
M
Sánchez
Félix
F
Vargas
Angel
A
Cogolludo
Juan
J
Tamargo
Francisco
F
Pérez-Vizcaíno
Juan
J
Duarte
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019332:Endothelin-1 / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D020556:Neutrophil Infiltration; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists* / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
D000109:Acetylcholine; D019332:Endothelin-1; D019255:NADPH Oxidases; D047494:PPAR delta; D048068:PPAR-beta; D009195:Peroxidase; D017382:Reactive Oxygen Species; D013311:Streptozocin; D013844:Thiazoles; D014280:Triglycerides; D014665:Vasodilator Agents; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds