Journal article
Ceramide-Initiated Protein Phosphatase 2A Activation Contributes to Arterial Dysfunction In Vivo
Diabetes (New York, N.Y.), Vol.64(11), pp.3914-3926
11/2015
DOI: 10.2337/db15-0244
PMCID: PMC4613970
PMID: 26253611
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.
Details
- Title: Subtitle
- Ceramide-Initiated Protein Phosphatase 2A Activation Contributes to Arterial Dysfunction In Vivo
- Creators
- Leena P Bharath - 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, UTTing Ruan - 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, UTYouyou Li - 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, UTAnindita Ravindran - 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, UTXin Wan - 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, UTJennifer Kim Nhan - 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, UTMatthew Lewis Walker - 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, UTLance Deeter - 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, UTRebekah Goodrich - 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, UTElizabeth Johnson - 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, UTDerek Munday - 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, UTRobert Mueller - 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, UTDavid Kunz - 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, UTDeborah Jones - Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UTVan Reese - The University of Utah Geriatric Research, Education, and Clinical Center, George E. Wahlen VA Medical Center, Salt Lake City, UTScott A Summers - Baker IDI Heart and Diabetes Institute, Melbourne, AustraliaPon Velayutham Anandh Babu - College of Health, The University of Utah, Salt Lake City, UTWilliam L Holland - Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TXQuan-Jiang Zhang - 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, IAE Dale Abel - 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, IAJ David Symons - 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
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.64(11), pp.3914-3926
- Publisher
- United States
- DOI
- 10.2337/db15-0244
- PMID
- 26253611
- PMCID
- PMC4613970
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Grant note
- R15 HL091493 / NHLBI NIH HHS R00 DK094973 / NIDDK NIH HHS T35 HL007744 / NHLBI NIH HHS R01 DK092065 / NIDDK NIH HHS U54 HL112311 / NHLBI NIH HHS 2R15HL091493 / NHLBI NIH HHS
- Language
- English
- Date published
- 11/2015
- 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
- 9984024501602771
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