title: Antihypertensive effects of peroxisome proliferator-activated receptor-β/δ activation.
abstract: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, which is composed of three members encoded by distinct genes: PPARα, PPARβ/δ, and PPARγ. The biological actions of PPARα and PPARγ and their potential as a cardiovascular therapeutic target have been extensively reviewed, whereas the biological actions of PPARβ/δ and its effectiveness as a therapeutic target in the treatment of hypertension remain less investigated. Preclinical studies suggest that pharmacological PPARβ/δ activation induces antihypertensive effects in direct [spontaneously hypertensive rat (SHR), ANG II, and DOCA-salt] and indirect (dyslipemic and gestational) models of hypertension, associated with end-organ damage protection. This review summarizes mechanistic insights into the antihypertensive effects of PPARβ/δ activators, including molecular and functional mechanisms. Pharmacological PPARβ/δ activation induces genomic actions including the increase of regulators of G protein-coupled signaling (RGS), acute nongenomic vasodilator effects, as well as the ability to improve the endothelial dysfunction, reduce vascular inflammation, vasoconstrictor responses, and sympathetic outflow from central nervous system. Evidence from clinical trials is also examined. These preclinical and clinical outcomes of PPARβ/δ ligands may provide a basis for the development of therapies in combating hypertension.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Toral
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.|Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA, Granada, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid. Spain; and.|Ciber Enfermedades Respiratorias (Ciberes). Madrid. Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.|Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA, Granada, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain; rjmoleon@ugr.es.|Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA, Granada, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Jiménez
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D007249:Inflammation; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D010642:Phenoxyacetates / Q000494:pharmacology / Q000627:therapeutic use; D020710:RGS Proteins / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D013564:Sympathetic Nervous System / Q000503:physiopathology; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D000959:Antihypertensive Agents; D005227:Fatty Acids; D047494:PPAR delta; D048068:PPAR-beta; D010642:Phenoxyacetates; D020710:RGS Proteins; D013844:Thiazoles; C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; C425931:GW 501516; 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
keywords: PPARβ/δ; endothelial dysfunction; hypertension; oxidative stress; vascular remodeling