Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex

Quan Jiang Zhang, William L. Holland, Lloyd Wilson, Jason M. Tanner, Devin Kearns, Judd M. Cahoon, Dix Pettey, Jason Losee, Bradlee Duncan, Derrick Gale, Christopher A. Kowalski, Nicholas Deeter, Alexandrea Nichols, Michole Deesing, Colton Arrant, Ting Ruan, Christoph Boehme, Dane R. McCamey, Janvida Rou, Kapil AmbalKrishna K. Narra, Scott A. Summers, E. Dale Abel, J. David Symons

Research output: Contribution to journalArticle

106 Citations (Scopus)

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 PP2Amediated 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.

Original languageEnglish (US)
Pages (from-to)1848-1859
Number of pages12
JournalDiabetes
Volume61
Issue number7
DOIs
StatePublished - Jul 2012

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Protein Phosphatase 2
Nitric Oxide Synthase Type III
Ceramides
Blood Vessels
Obesity
Diet
Phosphorylation
Transferases
Vasodilation
Endothelium
Insulin Resistance
Endothelial Cells
Arteries
Fats
Pharmacology
Hypertension
Lipids

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Zhang, Q. J., Holland, W. L., Wilson, L., Tanner, J. M., Kearns, D., Cahoon, J. M., ... Symons, J. D. (2012). Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. Diabetes, 61(7), 1848-1859. https://doi.org/10.2337/db11-1399

Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. / Zhang, Quan Jiang; Holland, William L.; Wilson, Lloyd; Tanner, Jason M.; Kearns, Devin; Cahoon, Judd M.; Pettey, Dix; Losee, Jason; Duncan, Bradlee; Gale, Derrick; Kowalski, Christopher A.; Deeter, Nicholas; Nichols, Alexandrea; Deesing, Michole; Arrant, Colton; Ruan, Ting; Boehme, Christoph; McCamey, Dane R.; Rou, Janvida; Ambal, Kapil; Narra, Krishna K.; Summers, Scott A.; Abel, E. Dale; Symons, J. David.

In: Diabetes, Vol. 61, No. 7, 07.2012, p. 1848-1859.

Research output: Contribution to journalArticle

Zhang, QJ, Holland, WL, Wilson, L, Tanner, JM, Kearns, D, Cahoon, JM, Pettey, D, Losee, J, Duncan, B, Gale, D, Kowalski, CA, Deeter, N, Nichols, A, Deesing, M, Arrant, C, Ruan, T, Boehme, C, McCamey, DR, Rou, J, Ambal, K, Narra, KK, Summers, SA, Abel, ED & Symons, JD 2012, 'Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex', Diabetes, vol. 61, no. 7, pp. 1848-1859. https://doi.org/10.2337/db11-1399
Zhang, Quan Jiang ; Holland, William L. ; Wilson, Lloyd ; Tanner, Jason M. ; Kearns, Devin ; Cahoon, Judd M. ; Pettey, Dix ; Losee, Jason ; Duncan, Bradlee ; Gale, Derrick ; Kowalski, Christopher A. ; Deeter, Nicholas ; Nichols, Alexandrea ; Deesing, Michole ; Arrant, Colton ; Ruan, Ting ; Boehme, Christoph ; McCamey, Dane R. ; Rou, Janvida ; Ambal, Kapil ; Narra, Krishna K. ; Summers, Scott A. ; Abel, E. Dale ; Symons, J. David. / Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. In: Diabetes. 2012 ; Vol. 61, No. 7. pp. 1848-1859.
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AU - Zhang, Quan Jiang

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AU - Wilson, Lloyd

AU - Tanner, Jason M.

AU - Kearns, Devin

AU - Cahoon, Judd M.

AU - Pettey, Dix

AU - Losee, Jason

AU - Duncan, Bradlee

AU - Gale, Derrick

AU - Kowalski, Christopher A.

AU - Deeter, Nicholas

AU - Nichols, Alexandrea

AU - Deesing, Michole

AU - Arrant, Colton

AU - Ruan, Ting

AU - Boehme, Christoph

AU - McCamey, Dane R.

AU - Rou, Janvida

AU - Ambal, Kapil

AU - Narra, Krishna K.

AU - Summers, Scott A.

AU - Abel, E. Dale

AU - Symons, J. David

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N2 - 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 PP2Amediated 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.

AB - 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 PP2Amediated 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.

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