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

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          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.

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          Most cited references 39

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          Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I.

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            Role of Akt signaling in vascular homeostasis and angiogenesis.

            Akt is a serine/threonine protein kinase that is activated by a number of growth factors and cytokines in a phosphatidylinositol-3 kinase-dependent manner. Although antiapoptotic activity of Akt is well known, it also regulates other aspects of cellular functions, including migration, glucose metabolism, and protein synthesis. In this review, Akt signaling in endothelial cells and its critical roles in the regulation of vascular homeostasis and angiogenesis will be discussed.
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              Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism.

              Obesity and dyslipidemia are risk factors for metabolic disorders including diabetes and cardiovascular disease. Sphingolipids such as ceramide and glucosylceramides, while being a relatively minor component of the lipid milieu in most tissues, may be among the most pathogenic lipids in the onset of the sequelae associated with excess adiposity. Circulating factors associated with obesity (e.g., saturated fatty acids, inflammatory cytokines) selectively induce enzymes that promote sphingolipid synthesis, and lipidomic profiling reveals relationships between tissue sphingolipid levels and certain metabolic diseases. Moreover, studies in cultured cells and isolated tissues implicate sphingolipids in certain cellular events associated with diabetes and cardiovascular disease, including insulin resistance, pancreatic beta-cell failure, cardiomyopathy, and vascular dysfunction. However, definitive evidence that sphingolipids contribute to insulin resistance, diabetes, and atherosclerosis has come only recently, as researchers have found that pharmacological inhibition or genetic ablation of enzymes controlling sphingolipid synthesis in rodents ameliorates each of these conditions. Herein we will review the role of ceramide and other sphingolipid metabolites in insulin resistance, beta-cell failure, cardiomyopathy, and vascular dysfunction, focusing on these in vivo studies that identify enzymes controlling sphingolipid metabolism as therapeutic targets for combating metabolic disease.

                Author and article information

                American Diabetes Association
                July 2012
                15 June 2012
                : 61
                : 7
                : 1848-1859
                1College of Health, University of Utah, Salt Lake City, Utah
                2Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah
                3Program in Molecular Medicine, University of Utah, Salt Lake City, Utah
                4Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas
                5Department of Physics and Astronomy, College of Science, University of Utah, Salt Lake City, Utah
                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
                Author notes
                Corresponding authors: E. Dale Abel, dale.abel@ , and J. David Symons, j.david.symons@ .
                © 2012 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.


                Endocrinology & Diabetes


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