title: Antihypertensive effects of peroxisome proliferator-activated receptor-β activation in spontaneously hypertensive rats.
abstract: Activation of nuclear hormone receptor peroxisome proliferator-activated receptor β/δ (PPARβ) has been shown to improve insulin resistance and plasma high-density lipoprotein levels, but nothing is known about its effects in genetic hypertension. We studied whether the PPARβ agonist GW0742 might exert antihypertensive effects in spontaneously hypertensive rats (SHRs). The rats were divided into 4 groups, Wistar Kyoto rat-control, Wistar Kyoto rat-treated (GW0742, 5 mg · kg(-1) · day(-1) by oral gavage), SHR-control, and SHR-treated, and followed for 5 weeks. GW0742 induced a progressive reduction in systolic arterial blood pressure and heart rate in SHRs and reduced the mesenteric arterial remodeling, the increased aortic vasoconstriction to angiotensin II, and the endothelial dysfunction characteristic of SHRs. These effects were accompanied by a significant increase in endothelial NO synthase activity attributed to upregulated endothelial NO synthase and downregulated caveolin 1 protein expression. Moreover, GW0742 inhibited vascular superoxide production, downregulated p22(phox) and p47(phox) proteins, decreased both basal and angiotensin II-stimulated NADPH oxidase activity, inhibited extracellular-regulated kinase 1/2 activation, and reduced the expression of the proinflammatory and proatherogenic genes, interleukin 1β, interleukin 6, or intercellular adhesion molecule 1. None of these effects were observed in Wistar Kyoto rats. PPARβ activation, both in vitro and in vivo, increased the expression of the regulators of G protein-coupled signaling proteins RGS4 and RGS5, which negatively modulated the vascular actions of angiotensin II. PPARβ activation exerted antihypertensive effects, restored the vascular structure and function, and reduced the oxidative, proinflammatory, and proatherogenic status of SHRs. We propose PPARβ as a new therapeutic target in hypertension.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Zarzuelo
authors.forename: Rosario
authors.initials: R
authors.lastname: Jiménez
authors.forename: Pilar
authors.initials: P
authors.lastname: Galindo
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez
authors.forename: Ana
authors.initials: A
authors.lastname: Nieto
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero
authors.forename: Ana María
authors.initials: AM
authors.lastname: Quintela
authors.forename: Rocío
authors.initials: R
authors.lastname: López-Sepúlveda
authors.forename: Manuel
authors.initials: M
authors.lastname: Gómez-Guzmán
authors.forename: Elvira
authors.initials: E
authors.lastname: Bailón
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodríguez-Gómez
authors.forename: Antonio
authors.initials: A
authors.lastname: Zarzuelo
authors.forename: Julio
authors.initials: J
authors.lastname: Gálvez
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D051242:Caveolin 1 / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D051242:Caveolin 1; D019204:GTP-Binding Proteins; D048052:Mitogen-Activated Protein Kinase 3; D052250:Nitric Oxide Synthase Type III; D048068:PPAR-beta; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D013844:Thiazoles; 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