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.
- Received February 24, 2016.
- Accepted April 25, 2016.
This work was supported by the Comisión Interministerial de Ciencia y Tecnología and Fondo Europeo de Desarrollo Regional [Grants SAF2010-22066-C02-01, SAF2011-28150, and SAF2014-55523-R]; Junta de Andalucía [Proyecto de excelencia, Grant P12-CTS-2722] with funds from the European Union; Ministerio de Ciencia e Innovación, Campus de Excelencia Internacional (Programa GREIB); and Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, Spain [Grants Red HERACLES RD06/0009 and RIC RD12/0042/0011]. C.D. is an Fonds National de la Recherche Scientifique (FNRS) FNRS senior research associate.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics