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Ceramide mediates vascular dysfunction in diet‐induced obesity by PP2A‐mediated dephosphorylation of the eNOS‐Akt complex
Author(s) -
Ruan Ting,
Ravindran Anindita,
Zhang Quan-Jiang,
Abel E Dale,
Symons J David
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1057.17
Subject(s) - enos , ceramide , protein phosphatase 2 , medicine , endocrinology , dephosphorylation , protein kinase b , phosphorylation , chemistry , endothelium , biology , microbiology and biotechnology , phosphatase , biochemistry , nitric oxide , nitric oxide synthase , apoptosis
Our prior studies reveal that pharmacological and genetic inhibition of de novo ceramide synthesis prevents vascular dysfunction in mice following high‐fat feeding and in isolated arteries incubated with palmitate, confirming that ceramide impairs endothelium‐dependent vasorelaxation in a tissue autonomous manner. Mechanisms were pursued in bovine aortic endothelial cells (ECs). De novo ceramide‐induced reductions in agonist‐stimulated eNOS phosphorylation or dimer formation, respectively, were independent of changes in activation of upstream kinases that phosphorylate eNOS (n=12–27), or superoxide anion‐mediated peroxynitrite formation (n=4–18). De novo ceramide biosynthesis increased the association of phosphatase 2A (PP2A) with the eNOS/Akt complex (p<0.05) and paralleled decreased (p<0.05) basal and agonist‐stimulated peNOS( S)1177 (n=12–34). Vascular p‐eNOS(S)1177 was lower (p<0.05), and PP2A association with eNOS was higher (p<0.05), in arteries of obese wild type mice vs. mice with targeted disruption of ceramide synthesis, indicating that similar mechanisms exist in vivo (9–13 mice/group). Moreover, in ECs PP2A attenuates p‐eNOS(S)1177 by preventing phosphorylation of the pool of Akt that co‐localizes with eNOS (p<0.05) and by dephosphorylating eNOS (p<0.05; n=12–18). Ceramide initiates this process by decreasing the association between PP2A and inhibitor 2 of PP2A (p<0.05; n=15–17). Thus ceramide might precipitate obesity‐related vascular dysfunction by a mechanism that involves PP2A‐mediated disruption of the eNOS/Akt signaling complex.