title: Ceramide-Initiated Protein Phosphatase 2A Activation Contributes to Arterial Dysfunction In Vivo.
abstract: Prior studies have implicated accumulation of ceramide in blood vessels as a basis for vascular dysfunction in diet-induced obesity via a mechanism involving type 2 protein phosphatase (PP2A) dephosphorylation of endothelial nitric oxide synthase (eNOS). The current study sought to elucidate the mechanisms linking ceramide accumulation with PP2A activation and determine whether pharmacological inhibition of PP2A in vivo normalizes obesity-associated vascular dysfunction and limits the severity of hypertension. We show in endothelial cells that ceramide associates with the inhibitor 2 of PP2A (I2PP2A) in the cytosol, which disrupts the association of I2PP2A with PP2A leading to its translocation to the plasma membrane. The increased association between PP2A and eNOS at the plasma membrane promotes dissociation of an Akt-Hsp90-eNOS complex that is required for eNOS phosphorylation and activation. A novel small-molecule inhibitor of PP2A attenuated PP2A activation, prevented disruption of the Akt-Hsp90-eNOS complex in the vasculature, preserved arterial function, and maintained normal blood pressure in obese mice. These findings reveal a novel mechanism whereby ceramide initiates PP2A colocalization with eNOS and demonstrate that PP2A activation precipitates vascular dysfunction in diet-induced obesity. Therapeutic strategies targeted to reducing PP2A activation might be beneficial in attenuating vascular complications that exist in the context of type 2 diabetes, obesity, and conditions associated with insulin resistance.
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT Molecular Medicine Program, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Leena P
authors.initials: LP
authors.lastname: Bharath
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Ting
authors.initials: T
authors.lastname: Ruan
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Youyou
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Anindita
authors.initials: A
authors.lastname: Ravindran
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Xin
authors.initials: X
authors.lastname: Wan
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Jennifer Kim
authors.initials: JK
authors.lastname: Nhan
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Matthew Lewis
authors.initials: ML
authors.lastname: Walker
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Lance
authors.initials: L
authors.lastname: Deeter
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Goodrich
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Johnson
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Derek
authors.initials: D
authors.lastname: Munday
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Robert
authors.initials: R
authors.lastname: Mueller
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: David
authors.initials: D
authors.lastname: Kunz
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Deborah
authors.initials: D
authors.lastname: Jones
authors.affiliation: The University of Utah Geriatric Research, Education, and Clinical Center, George E. Wahlen VA Medical Center, Salt Lake City, UT.
authors.forename: Van
authors.initials: V
authors.lastname: Reese
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT.
authors.forename: Pon Velayutham Anandh
authors.initials: PV
authors.lastname: Babu
authors.affiliation: Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.affiliation: Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA.
authors.forename: Quan-Jiang
authors.initials: QJ
authors.lastname: Zhang
authors.affiliation: Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.affiliation: College of Health, The University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT Molecular Medicine Program, The University of Utah School of Medicine, Salt Lake City, UT j.david.symons@hsc.utah.edu.
authors.forename: J David
authors.initials: JD
authors.lastname: Symons
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D018841:HSP90 Heat-Shock Proteins; D019308:Palmitic Acid; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; C001996:thermozymocidin