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. Epub 2016 Jul 13.

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.

Keywords: PPARβ/δ; cAMP; cardiovascular system; coronary circulation; diabetes mellitus; oxidative stress; potassium channels.

MeSH terms

  • Animals
  • Coronary Vessels / drug effects
  • Coronary Vessels / metabolism*
  • Coronary Vessels / physiopathology
  • Cyclic AMP / metabolism*
  • Diabetes Mellitus, Experimental
  • Humans
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism*
  • KCNQ1 Potassium Channel / genetics
  • KCNQ1 Potassium Channel / metabolism*
  • Male
  • PPAR delta / genetics
  • PPAR delta / metabolism*
  • PPAR-beta / genetics
  • PPAR-beta / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Thiazoles / administration & dosage
  • Vasodilation / drug effects

Substances

  • GW0742
  • KCNQ1 Potassium Channel
  • PDK4 protein, human
  • PPAR delta
  • PPAR-beta
  • Pdk4 protein, rat
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Reactive Oxygen Species
  • Thiazoles
  • Cyclic AMP
  • Protein-Serine-Threonine Kinases