Activation of PPARβ/δ prevents hyperglycaemia-induced impairment of Kv7 channels and cAMP-mediated relaxation in rat coronary arteries

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dc.contributor.authorMorales Cano, Daniel
dc.contributor.authorMoreno Gutiérrez, Laura
dc.contributor.authorBarreira, Bianca
dc.contributor.authorPandolfi, Rachele
dc.contributor.authorMoral Sanz, Javier
dc.contributor.authorCallejo Arranz, María
dc.contributor.authorMondejar Parreño, Gema
dc.contributor.authorPérez Vizcaíno, Francisco
dc.contributor.authorCogolludo Torralba, Ángel Luis
dc.date.accessioned2024-02-01T11:16:50Z
dc.date.available2024-02-01T11:16:50Z
dc.date.issued2016-09-15
dc.description.abstractPPARβ/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 functionen
dc.description.departmentDepto. de Farmacología y Toxicología
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.statuspub
dc.identifier.citationMorales-Cano D, Moreno L, Barreira B, Briones AM, Pandolfi R, Moral-Sanz J, Callejo M, Mondejar-Parreño G, Cortijo J, Salaices M, Duarte J, Perez-Vizcaino F, Cogolludo A. Activation of PPARβ/δ prevents hyperglycaemia-induced impairment of Kv7 channels and cAMP-mediated relaxation in rat coronary arteries. Clin Sci (Lond). 2016 Oct 1;130(20):1823-36. doi: 10.1042/CS20160141
dc.identifier.doi10.1042/cs20160141
dc.identifier.issn0143-5221
dc.identifier.issn1470-8736
dc.identifier.officialurlhttps//doi.org/10.1042/cs20160141
dc.identifier.relatedurlhttps://portlandpress.com/clinsci/article-abstract/130/20/1823/71440/Activation-of-PPAR-prevents-hyperglycaemia-induced?redirectedFrom=fulltext
dc.identifier.relatedurlhttps://pubmed.ncbi.nlm.nih.gov/27413020/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/97585
dc.issue.number20
dc.journal.titleClinical Science
dc.language.isoeng
dc.page.final1826
dc.page.initial1823
dc.publisherPortland Press
dc.rights.accessRightsembargoed access
dc.subject.cdu615.01/.03
dc.subject.keywordPPARβ/δ
dc.subject.keywordcAMP
dc.subject.keywordCardiovascular system
dc.subject.keywordCoronary circulation
dc.subject.keywordDiabetes mellitus
dc.subject.keywordOxidative stress
dc.subject.keywordPotassium channels
dc.subject.ucmFarmacología (Medicina)
dc.subject.unesco2411.03 Fisiología Cardiovascular
dc.titleActivation of PPARβ/δ prevents hyperglycaemia-induced impairment of Kv7 channels and cAMP-mediated relaxation in rat coronary arteriesen
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number130
dspace.entity.typePublication
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