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.
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October 2016
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Targeted cancer treatment. In this issue, Gopal et al, review the molecular mechanisms of vascular complications of targeted cancer therapies. See pp. 1763–1779 for further details.
Research Article|
September 15 2016
Activation of PPARβ/δ prevents hyperglycaemia-induced impairment of Kv7 channels and cAMP-mediated relaxation in rat coronary arteries
Daniel Morales-Cano;
Daniel Morales-Cano
1
*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
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Laura Moreno;
Laura Moreno
1
*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
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Bianca Barreira;
Bianca Barreira
*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
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Ana M. Briones;
Ana M. Briones
‡Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Hospital La Paz (IdiPAZ), University Autonoma Madrid, 28029 Madrid, Spain
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Rachele Pandolfi;
Rachele Pandolfi
*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
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Javier Moral-Sanz;
Javier Moral-Sanz
*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
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Maria Callejo;
Maria Callejo
*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
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Gema Mondejar-Parreño;
Gema Mondejar-Parreño
*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
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Julio Cortijo;
Julio Cortijo
†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
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Mercedes Salaices;
Mercedes Salaices
‡Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Hospital La Paz (IdiPAZ), University Autonoma Madrid, 28029 Madrid, Spain
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Juan Duarte;
Juan Duarte
¶Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain
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Francisco Perez-Vizcaino;
Francisco Perez-Vizcaino
*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
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Angel Cogolludo
*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
Correspondence: Angel Cogolludo (email acogolludo@med.ucm.es).
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Publisher: Portland Press Ltd
Received:
February 22 2016
Revision Received:
June 14 2016
Accepted:
July 13 2016
Accepted Manuscript online:
July 13 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (20): 1823–1836.
Article history
Received:
February 22 2016
Revision Received:
June 14 2016
Accepted:
July 13 2016
Accepted Manuscript online:
July 13 2016
Connected Content
This is a commentary on:
Vascular smooth muscle cell dysfunction in diabetes: nuclear receptors channel to relaxation
Citation
Daniel Morales-Cano, Laura Moreno, Bianca Barreira, Ana M. Briones, Rachele Pandolfi, Javier Moral-Sanz, Maria Callejo, Gema Mondejar-Parreño, Julio Cortijo, Mercedes Salaices, Juan Duarte, Francisco Perez-Vizcaino, Angel Cogolludo; Activation of PPARβ/δ prevents hyperglycaemia-induced impairment of Kv7 channels and cAMP-mediated relaxation in rat coronary arteries. Clin Sci (Lond) 1 October 2016; 130 (20): 1823–1836. doi: https://doi.org/10.1042/CS20160141
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