title: Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex.
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.
authors.affiliation: College of Health, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Quan-Jiang
authors.initials: QJ
authors.lastname: Zhang
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.forename: Lloyd
authors.initials: L
authors.lastname: Wilson
authors.forename: Jason M
authors.initials: JM
authors.lastname: Tanner
authors.forename: Devin
authors.initials: D
authors.lastname: Kearns
authors.forename: Judd M
authors.initials: JM
authors.lastname: Cahoon
authors.forename: Dix
authors.initials: D
authors.lastname: Pettey
authors.forename: Jason
authors.initials: J
authors.lastname: Losee
authors.forename: Bradlee
authors.initials: B
authors.lastname: Duncan
authors.forename: Derrick
authors.initials: D
authors.lastname: Gale
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Kowalski
authors.forename: Nicholas
authors.initials: N
authors.lastname: Deeter
authors.forename: Alexandrea
authors.initials: A
authors.lastname: Nichols
authors.forename: Michole
authors.initials: M
authors.lastname: Deesing
authors.forename: Colton
authors.initials: C
authors.lastname: Arrant
authors.forename: Ting
authors.initials: T
authors.lastname: Ruan
authors.forename: Christoph
authors.initials: C
authors.lastname: Boehme
authors.forename: Dane R
authors.initials: DR
authors.lastname: McCamey
authors.forename: Janvida
authors.initials: J
authors.lastname: Rou
authors.forename: Kapil
authors.initials: K
authors.lastname: Ambal
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Narra
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: J David
authors.initials: JD
authors.lastname: Symons
mesh_terms: D000818:Animals; D002417:Cattle; D002518:Ceramides / Q000096:biosynthesis*; D059305:Diet, High-Fat; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D018841:HSP90 Heat-Shock Proteins; D010088:Oxidoreductases; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C108138:dihydroceramide desaturase; D051102:Serine C-Palmitoyltransferase; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; C001996:thermozymocidin