Fatty acids cause endothelial dysfunction involving increased ROS (reactive oxygen species) and reduced NO (nitric oxide) bioavailability. We show that in MAECs (mouse aortic endothelial cells), the PPARβ/δ (peroxisome- proliferator-activated receptor β/δ) agonist GW0742 prevented the decreased A23187-stimulated NO production, phosphorylation of eNOS (endothelial nitric oxide synthase) at Ser1177 and increased intracellular ROS levels caused by exposure to palmitate in vitro. The impaired endothelium-dependent relaxation to acetylcholine in mouse aorta induced by palmitate was restored by GW0742. In vivo, GW0742 treatment prevented the reduced aortic relaxation, phosphorylation of eNOS at Ser1177, and increased ROS production and NADPH oxidase in mice fed on a high-fat diet. The PPARβ/δ antagonist GSK0660 abolished all of these protective effects induced by GW0742. This agonist enhanced the expression of CPT (carnitine palmitoyltransferase)-1. The effects of GW0742 on acetylcholine- induced relaxation in aorta and on NO and ROS production in MAECs exposed to palmitate were abolished by the CPT-1 inhibitor etomoxir or by siRNA targeting CPT-1. GW0742 also inhibited the increase in DAG (diacylglycerol), PKCα/βII (protein kinase Cα/βII) activation, and phosphorylation of eNOS at Thr495 induced by palmitate in MAECs, which were abolished by etomoxir. In conclusion, PPARβ/δ activation restored the lipid-induced endothelial dysfunction by up-regulation of CPT-1, thus reducing DAG accumulation and the subsequent PKC-mediated ROS production and eNOS inhibition.
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August 07 2015
Carnitine palmitoyltransferase-1 up-regulation by PPAR-β/δ prevents lipid-induced endothelial dysfunction
Marta Toral;
Marta Toral
1
*Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain
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Miguel Romero;
Miguel Romero
1
*Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain
†Instituto de Investigación Biosanitaria de Granada, Granada, Spain
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Rosario Jiménez;
Rosario Jiménez
*Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain
†Instituto de Investigación Biosanitaria de Granada, Granada, Spain
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Ayman Moawad Mahmoud;
Ayman Moawad Mahmoud
*Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain
‡Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, 62511 Beni-Suef, Egypt
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Emma Barroso;
Emma Barroso
§Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain
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Manuel Gómez-Guzmán;
Manuel Gómez-Guzmán
*Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain
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Manuel Sánchez;
Manuel Sánchez
*Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain
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Ángel Cogolludo;
Ángel Cogolludo
║Department of Pharmacology, School of Medicine, University Complutense of Madrid, Ciber Enfermedades Respiratorias (Ciberes), 28040 Madrid, Spain
¶Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain
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Ana B. García-Redondo;
Ana B. García-Redondo
**Department of Pharmacology, University Autónoma of Madrid, 28029 Madrid, Spain
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Ana M. Briones;
Ana M. Briones
**Department of Pharmacology, University Autónoma of Madrid, 28029 Madrid, Spain
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Manuel Vázquez-Carrera;
Manuel Vázquez-Carrera
§Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain
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Francisco Pérez-Vizcaíno;
Francisco Pérez-Vizcaíno
║Department of Pharmacology, School of Medicine, University Complutense of Madrid, Ciber Enfermedades Respiratorias (Ciberes), 28040 Madrid, Spain
¶Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain
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Juan Duarte
*Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain
†Instituto de Investigación Biosanitaria de Granada, Granada, Spain
Correspondence: Dr Juan Duarte (email [email protected]).
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Publisher: Portland Press Ltd
Received:
February 03 2015
Revision Received:
June 16 2015
Accepted:
July 03 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2015 Authors; published by Portland Press Limited
2015
Clin Sci (Lond) (2015) 129 (9): 823–837.
Article history
Received:
February 03 2015
Revision Received:
June 16 2015
Accepted:
July 03 2015
Citation
Marta Toral, Miguel Romero, Rosario Jiménez, Ayman Moawad Mahmoud, Emma Barroso, Manuel Gómez-Guzmán, Manuel Sánchez, Ángel Cogolludo, Ana B. García-Redondo, Ana M. Briones, Manuel Vázquez-Carrera, Francisco Pérez-Vizcaíno, Juan Duarte; Carnitine palmitoyltransferase-1 up-regulation by PPAR-β/δ prevents lipid-induced endothelial dysfunction. Clin Sci (Lond) 1 November 2015; 129 (9): 823–837. doi: https://doi.org/10.1042/CS20150111
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