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

Quan-Jiang Zhang1, William L Holland, Lloyd Wilson

  • 1College of Health, University of Utah, Salt Lake City, Utah, USA.

Diabetes
|May 16, 2012
PubMed

Insights

Vascular dysfunction in obesity is linked to ceramides. Inhibiting ceramide synthesis reversed arterial dysfunction and hypertension in mice by preserving endothelial nitric oxide synthase signaling.

Area of Science:

  • Biochemistry
  • Cardiovascular Biology
  • Metabolic Disease Research

Background:

  • Obesity and insulin resistance are associated with vascular dysfunction, potentially mediated by lipid metabolites.
  • Ceramides, a class of lipid metabolites, are implicated in cellular dysfunction.

Purpose of the Study:

  • To investigate if vascular ceramides contribute to arterial dysfunction.
  • To elucidate the molecular mechanisms by which ceramides impair vascular function.

Main Methods:

  • Pharmacological inhibition of de novo ceramide synthesis using myriocin.
  • Genetic deletion of dihydroceramide desaturase in mice.
  • In vitro studies using isolated arteries and endothelial cells.

Main Results:

  • Inhibition of ceramide synthesis prevented vascular dysfunction and hypertension in high-fat-fed mice.
  • Ceramide impaired endothelium-dependent vasorelaxation in isolated arteries.
  • Ceramide disrupted the endothelial nitric oxide synthase (eNOS)/Akt/Hsp90 complex via protein phosphatase 2A (PP2A) in endothelial cells, reducing eNOS phosphorylation.

Conclusions:

  • Ceramide mediates obesity-related vascular dysfunction through PP2A-dependent disruption of the eNOS/Akt/Hsp90 signaling complex.
  • Targeting ceramide synthesis offers a novel therapeutic strategy for reversing obesity-associated vascular dysfunction.

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