title: Vascular and Central Activation of Peroxisome Proliferator-Activated Receptor-β Attenuates Angiotensin II-Induced Hypertension: Role of RGS-5.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Rosario
authors.initials: R
authors.lastname: Jiménez
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Marta
authors.initials: M
authors.lastname: Toral
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Elvira
authors.initials: E
authors.lastname: León-Gómez
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Manuel
authors.initials: M
authors.lastname: Gómez-Gúzman
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: María José
authors.initials: MJ
authors.lastname: Zarzuelo
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodríguez-Gómez
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Geraldine
authors.initials: G
authors.lastname: Rath
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.).
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
authors.affiliation: Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.) jmduarte@ugr.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000097:blood; D048068:PPAR-beta / Q000819:agonists* / Q000037:antagonists & inhibitors; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D000804:Angiotensin II; D000959:Antihypertensive Agents; D009638:Norepinephrine; D048068:PPAR-beta; D020710:RGS Proteins; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; C529769:GSK0660; C105346:Rgs5 protein, mouse; 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