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Show 136 Ting Ruan school of medicine and health sciences Our prior studies reveal that pharmacological and genetic inhibition of de novo ceramide synthesis pre-vents vascular dysfunction in mice following high-fat feeding and in isolated arteries incubated with pal-mitate, confirming that ceramide impairs endothelium-dependent vasorelaxation in a tissue autonomous manner. Mechanisms were pursued in bovine aortic endothelial cells (BAECs). De novo ceramide-induced reductions in agonist-stimulated eNOS phosphorylation or dimer formation, respectively, were indepen-dent of changes in activation of upstream kinases that phosphorylate endothelial nitric oxide (NO) syn-thase (eNOS; n=12-27), or superoxide anion-mediated peroxynitrite formation (n=4-18). De novo ceramide biosynthesis increased the association of protein phosphatase 2A (PP2A) with the eNOS-Akt complex (p<0.05) and paralleled decreased (p<0.05) basal and agonist-stimulated p-eNOS(S)1177 (n=12-34). Vascu-lar 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 mech-anisms exist in vivo (9-13 mice/group). Moreover, in BAECs 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 inhibi-tor 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. CERAMIDE MEDIATES VASCULAR DYSFUNCTION IN DIET-INDUCED OBESITY BY PP2A-MEDIATED DEPHOSPHORYLATION OF THE eNOS-Akt COMPLEX Ting Ruan, (J. David Symons) Division of Endocrinology, Metabolism and Diabetes, School of Medicine University of Utah UNDERGRADUATE RESEARCH ABSTRACTS J. David Symons |