Journal article
Ceramide Mediates Vascular Dysfunction in Diet-Induced Obesity by PP2A-Mediated Dephosphorylation of the eNOS-Akt Complex
Diabetes (New York, N.Y.), Vol.61(7), pp.1848-1859
2012
DOI: 10.2337/db11-1399
PMCID: PMC3379648
PMID: 22586587
Abstract
Vascular dysfunction that accompanies obesity and insulin resistance may be mediated by lipid metabolites. We sought to determine if vascular ceramide leads to arterial dysfunction and to elucidate the underlying mechanisms. Pharmacological inhibition of de novo ceramide synthesis, using the Ser palmitoyl transferase inhibitor myriocin, and heterozygous deletion of dihydroceramide desaturase prevented vascular dysfunction and hypertension in mice after high-fat feeding. These findings were recapitulated in isolated arteries in vitro, confirming that ceramide impairs endothelium-dependent vasorelaxation in a tissue-autonomous manner. Studies in endothelial cells reveal that de novo ceramide biosynthesis induced protein phosphatase 2A (PP2A) association directly with the endothelial nitric oxide synthase (eNOS)/Akt/Hsp90 complex that was concurrent with decreased basal and agonist-stimulated eNOS phosphorylation. PP2A attenuates eNOS phosphorylation by preventing phosphorylation of the pool of Akt that colocalizes with eNOS and by dephosphorylating eNOS. Ceramide decreased the association between PP2A and the predominantly cytosolic inhibitor 2 of PP2A. We conclude that ceramide mediates obesity-related vascular dysfunction by a mechanism that involves PP2A-mediated disruption of the eNOS/Akt/Hsp90 signaling complex. These results provide important insight into a pathway that represents a novel target for reversing obesity-related vascular dysfunction.
Details
- Title: Subtitle
- Ceramide Mediates Vascular Dysfunction in Diet-Induced Obesity by PP2A-Mediated Dephosphorylation of the eNOS-Akt Complex
- Creators
- Quan-Jiang ZHANG - College of Health, University of Utah, Salt Lake City, Utah, United StatesWilliam L HOLLAND - Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, United StatesChristopher A KOWALSKI - College of Health, University of Utah, Salt Lake City, Utah, United StatesNicholas DEETER - College of Health, University of Utah, Salt Lake City, Utah, United StatesAlexandrea NICHOLS - College of Health, University of Utah, Salt Lake City, Utah, United StatesMichole DEESING - College of Health, University of Utah, Salt Lake City, Utah, United StatesColton ARRANT - College of Health, University of Utah, Salt Lake City, Utah, United StatesTing RUAN - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah, United StatesChristoph BOEHME - Department of Physics and Astronomy, College of Science, University of Utah, Salt Lake City, Utah, United StatesDane R MCCAMEY - Department of Physics and Astronomy, College of Science, University of Utah, Salt Lake City, Utah, United StatesJanvida ROU - Department of Physics and Astronomy, College of Science, University of Utah, Salt Lake City, Utah, United StatesKapil AMBAL - Department of Physics and Astronomy, College of Science, University of Utah, Salt Lake City, Utah, United StatesLloyd WILSON - College of Health, University of Utah, Salt Lake City, Utah, United StatesKrishna K NARRA - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah, United StatesScott A SUMMERS - Program in Cardiovascular and Metabolic Diseases, Duke-NUS Graduate Medical School, SingaporeE. Dale ABEL - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah, United StatesJ. David SYMONS - College of Health, University of Utah, Salt Lake City, Utah, United StatesJason M TANNER - College of Health, University of Utah, Salt Lake City, Utah, United StatesDevin KEARNS - College of Health, University of Utah, Salt Lake City, Utah, United StatesJudd M CAHOON - College of Health, University of Utah, Salt Lake City, Utah, United StatesDix PETTEY - College of Health, University of Utah, Salt Lake City, Utah, United StatesJason LOSEE - College of Health, University of Utah, Salt Lake City, Utah, United StatesBradlee DUNCAN - College of Health, University of Utah, Salt Lake City, Utah, United StatesDerrick GALE - College of Health, University of Utah, Salt Lake City, Utah, United States
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.61(7), pp.1848-1859
- Publisher
- American Diabetes Association; Alexandria, VA
- DOI
- 10.2337/db11-1399
- PMID
- 22586587
- PMCID
- PMC3379648
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Language
- English
- Date published
- 2012
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024511102771
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