Ceramide Mediates Vascular Dysfunction in Diet-Induced Obesity by PP2A-Mediated Dephosphorylation of the eNOS-Akt Complex

  1. J. David Symons1,2
  1. 1College of Health, University of Utah, Salt Lake City, Utah
  2. 2Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah
  3. 3Program in Molecular Medicine, University of Utah, Salt Lake City, Utah
  4. 4Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas
  5. 5Department of Physics and Astronomy, College of Science, University of Utah, Salt Lake City, Utah
  6. 6Program in Cardiovascular and Metabolic Diseases, Duke-NUS Graduate Medical School, Singapore, and the Stedman Center for Nutrition and Metabolism Research, Duke University Medical Center, Durham, North Carolina
  1. Corresponding authors: E. Dale Abel, dale.abel{at}hmbg.utah.edu, and J. David Symons, j.david.symons{at}hsc.utah.edu.
  1. Q.-J.Z. and W.L.H. contributed equally to the study.

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.

Footnotes

  • Received October 4, 2011.
  • Accepted February 29, 2012.

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