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Carnitine palmitoyltransferase-1 up-regulation by PPAR-β/δ prevents lipid-induced endothelial dysfunction.
Clin Sci (Lond). 2015 Nov; 129(9):823-37.CS

Abstract

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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Authors+Show Affiliations

Toral M
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
Romero M
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain Instituto de Investigación Biosanitaria de Granada, Granada, Spain.
Jiménez R
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain Instituto de Investigación Biosanitaria de Granada, Granada, Spain.
Mahmoud AM
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.
Barroso E
Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.
Gómez-Guzmán M
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
Sánchez M
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
Cogolludo Á
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.
García-Redondo AB
Department of Pharmacology, University Autónoma of Madrid, 28029 Madrid, Spain.
Briones AM
Department of Pharmacology, University Autónoma of Madrid, 28029 Madrid, Spain.
Vázquez-Carrera M
Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.
Pérez-Vizcaíno F
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.
Duarte J
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain Instituto de Investigación Biosanitaria de Granada, Granada, Spain jmduarte@ugr.es.

MeSH

AnimalsAortaBlotting, WesternCalcimycinCarnitine O-PalmitoyltransferaseCells, CulturedDiglyceridesEndothelium, VascularEnzyme ActivationLipidsMaleMiceMice, Inbred C57BLNitric OxideNitric Oxide Synthase Type IIIPPAR deltaPPAR-betaPalmitic AcidsPhosphorylationProtein Kinase C-alphaRNA InterferenceReactive Oxygen SpeciesSulfonesThiazolesThiophenesUp-Regulation

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26253087

Citation

Toral, Marta, et al. "Carnitine Palmitoyltransferase-1 Up-regulation By PPAR-β/δ Prevents Lipid-induced Endothelial Dysfunction." Clinical Science (London, England : 1979), vol. 129, no. 9, 2015, pp. 823-37.
Toral M, Romero M, Jiménez R, et al. Carnitine palmitoyltransferase-1 up-regulation by PPAR-β/δ prevents lipid-induced endothelial dysfunction. Clin Sci (Lond). 2015;129(9):823-37.
Toral, M., Romero, M., Jiménez, R., Mahmoud, A. M., Barroso, E., Gómez-Guzmán, M., Sánchez, M., Cogolludo, Á., García-Redondo, A. B., Briones, A. M., Vázquez-Carrera, M., Pérez-Vizcaíno, F., & Duarte, J. (2015). Carnitine palmitoyltransferase-1 up-regulation by PPAR-β/δ prevents lipid-induced endothelial dysfunction. Clinical Science (London, England : 1979), 129(9), 823-37. https://doi.org/10.1042/CS20150111
Toral M, et al. Carnitine Palmitoyltransferase-1 Up-regulation By PPAR-β/δ Prevents Lipid-induced Endothelial Dysfunction. Clin Sci (Lond). 2015;129(9):823-37. PubMed PMID: 26253087.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carnitine palmitoyltransferase-1 up-regulation by PPAR-β/δ prevents lipid-induced endothelial dysfunction. AU - Toral,Marta, AU - Romero,Miguel, AU - Jiménez,Rosario, AU - Mahmoud,Ayman Moawad, AU - Barroso,Emma, AU - Gómez-Guzmán,Manuel, AU - Sánchez,Manuel, AU - Cogolludo,Ángel, AU - García-Redondo,Ana B, AU - Briones,Ana M, AU - Vázquez-Carrera,Manuel, AU - Pérez-Vizcaíno,Francisco, AU - Duarte,Juan, PY - 2015/8/9/entrez PY - 2015/8/9/pubmed PY - 2015/11/18/medline KW - CPT-1 KW - NADPH oxidase KW - PPARβ/δ. KW - endothelial dysfunction KW - lipids KW - mitochondrial ROS SP - 823 EP - 37 JF - Clinical science (London, England : 1979) JO - Clin Sci (Lond) VL - 129 IS - 9 N2 - 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. SN - 1470-8736 UR - https://www.unboundmedicine.com/medline/citation/26253087/Carnitine_palmitoyltransferase_1_up_regulation_by_PPAR_β/δ_prevents_lipid_induced_endothelial_dysfunction_ L2 - https://portlandpress.com/clinsci/article-lookup/doi/10.1042/CS20150111 DB - PRIME DP - Unbound Medicine ER -