RT Journal Article
T1 Activation of PPARβ/δ prevents hyperglycaemia-induced impairment of Kv7 channels and cAMP-mediated relaxation in rat coronary arteries
A1 Morales Cano, Daniel
A1 Moreno Gutiérrez, Laura
A1 Barreira, Bianca
A1 Pandolfi, Rachele
A1 Moral Sanz, Javier
A1 Callejo Arranz, María
A1 Mondejar Parreño, Gema
A1 Pérez Vizcaíno, Francisco
A1 Cogolludo Torralba, Ángel Luis
AB 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
PB Portland Press
SN 0143-5221
SN 1470-8736
YR 2016
FD 2016-09-15
LK https://hdl.handle.net/20.500.14352/97585
UL https://hdl.handle.net/20.500.14352/97585
LA eng
NO Morales-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
DS Docta Complutense
RD 17 ago 2024