PT  - JOURNAL ARTICLE
AU  - Miguel Romero
AU  - Rosario Jiménez
AU  - Marta Toral
AU  - Elvira León-Gómez
AU  - Manuel Gómez-Gúzman
AU  - Manuel Sánchez
AU  - María José Zarzuelo
AU  - Isabel Rodríguez-Gómez
AU  - Geraldine Rath
AU  - Juan Tamargo
AU  - Francisco Pérez-Vizcaíno
AU  - Chantal Dessy
AU  - Juan Duarte
TI  - Vascular and Central Activation of Peroxisome Proliferator–Activated Receptor-<em>β</em> Attenuates Angiotensin II–Induced Hypertension: Role of RGS-5
AID  - 10.1124/jpet.116.233106
DP  - 2016 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 151--163
VI  - 358
IP  - 1
4099  - http://jpet.aspetjournals.org/content/358/1/151.short
4100  - http://jpet.aspetjournals.org/content/358/1/151.full
SO  - J Pharmacol Exp Ther2016 Jul 01; 358
AB  - Activation of peroxisome proliferator–activated receptor-β/δ (PPARβ) lowers blood pressure in genetic and mineralocorticoid-induced hypertension. Regulator of G-protein-coupled receptor signaling 5 (RGS5) protein, which interferes in angiotensin II (AngII) signaling, is a target gene to PPARβ. The aim of the present study was to examine whether PPARβ activation in resistance arteries and brain tissues prevents the elevated blood pressure in AngII-induced hypertension and evaluate the role of RGS5 in this effect. C57BL/6J male mice were divided into five groups (control mice, PPARβ agonist [4-[[[2-[3-Fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742)-treated mice AngII-infused mice, GW0742-treated AngII-infused mice, and AngII-infused mice treated with GW0742 plus PPARβ antagonist 3-[[[2-Methoxy-4-(phenylamino)phenyl]amino]sulfonyl]-2-thiophenecarboxylic acid methyl ester (GSK0660)) and were followed for 3 weeks. GW0742 prevented the increase in both arterial blood pressure and plasma noradrenaline levels and the higher reduction of blood pressure after ganglionic blockade, whereas it reduced the mesenteric arterial remodeling and the hyper-responsiveness to vasoconstrictors (AngII and endothelin-1) in AngII-infused mice. These effects were accompanied by an inhibition of NADPH oxidase expression and activity in the brain. Gene expression profiling revealed a marked loss of brainstem and vascular RGS5 in AngII-infused mice, which was restored by GW0742. GW0742-induced effects were abolished by GSK0660. Small interfering RNA targeting RGS5 caused augmented contractile response to AngII in resistance mesenteric arteries and blunted the inhibitory effect of GW0742 on this response. In conclusion, GW0742 exerted antihypertensive effects, restoring sympathetic tone and vascular structure and function in AngII-infused mice by PPARβ activation in brain and vessels inhibiting AngII signaling as a result of RGS5 upregulation.