title: Activation of PPARβ/δ prevents hyperglycaemia-induced impairment of Kv7 channels and cAMP-mediated relaxation in rat coronary arteries.
abstract: PPARβ/δ activation protects against endothelial dysfunction in diabetic models. Elevated glucose is known to impair cAMP-induced relaxation and Kv channel function in coronary arteries (CA). Herein, we aimed to analyse the possible protective effects of the PPARβ/δ agonist GW0742 on the hyperglycaemic-induced impairment of cAMP-induced relaxation and Kv channel function in rat CA. As compared with low glucose (LG), incubation under high glucose (HG) conditions attenuated the relaxation induced by the adenylate cyclase activator forskolin in CA and this was prevented by GW0742. The protective effect of GW0742 was supressed by a PPARβ/δ antagonist. In myocytes isolated from CA under LG, forskolin enhanced Kv currents and induced hyperpolarization. In contrast, when CA were incubated with HG, Kv currents were diminished and the electrophysiological effects of forskolin were abolished. These deleterious effects were prevented by GW0742. The protective effects of GW0742 on forskolin-induced relaxation and Kv channel function were confirmed in CA from type-1 diabetic rats. In addition, the differences in the relaxation induced by forskolin in CA incubated under LG, HG or HG + GW0742 were abolished by the Kv7 channel inhibitor XE991. Accordingly, GW0742 prevented the down-regulation of Kv7 channels induced by HG. Finally, the preventive effect of GW0742 on oxidative stress and cAMP-induced relaxation were overcome by the pyruvate dehydrogenase kinase 4 (PDK4) inhibitor dichloroacetate (DCA). Our results reveal that the PPARβ/δ agonist GW0742 prevents the impairment of the cAMP-mediated relaxation in CA under HG. This protective effect was associated with induction of PDK4, attenuation of oxidative stress and preservation of Kv7 channel function.
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morales-Cano
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Moreno
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
authors.forename: Bianca
authors.initials: B
authors.lastname: Barreira
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Hospital La Paz (IdiPAZ), University Autonoma Madrid, 28029 Madrid, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Briones
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
authors.forename: Rachele
authors.initials: R
authors.lastname: Pandolfi
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Moral-Sanz
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Callejo
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Mondejar-Parreño
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain Clinical Research Unit, University General Hospital Consortium, 46014 Valencia, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Hospital La Paz (IdiPAZ), University Autonoma Madrid, 28029 Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Perez-Vizcaino
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain acogolludo@med.ucm.es.
authors.forename: Angel
authors.initials: A
authors.lastname: Cogolludo
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008297:Male; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage; D014664:Vasodilation / Q000187:drug effects; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D000242:Cyclic AMP; D051657:KCNQ1 Potassium Channel; D047494:PPAR delta; D048068:PPAR-beta; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D013844:Thiazoles; C000631432:PDK4 protein, human; C000631440:Pdk4 protein, rat; 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; cAMP; cardiovascular system; coronary circulation; diabetes mellitus; oxidative stress; potassium channels