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Saturated, but Not Unsaturated, Fatty Acids Induce Apoptosis of Human Coronary Artery Endothelial Cells via Nuclear Factor-B Activation

¹ Division of Endocrinology, Metabolism, and Pathobiochemistry, Department of Internal Medicine, Eberhard-Karls University Tübingen, Tübingen, Germany
² Clinic of Diabetology, Endocrinology, Intensive Care Medicine, Vascular Medicine, and Cardiology, Center for Internal Medicine I, Marienhospital Stuttgart, Stuttgart, Germany

Address correspondence and reprint requests to Dr. Monika Kellerer, Internal Medicine IV, Medical Clinic, University of Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail: monikakellerer{at}vinzenz.de

Abbreviations: HCAEC, human coronary artery endothelial cell; HUVEC, human umbilical vein endothelial cell; IKK, inhibitor of B kinase; IL, interleukin; NEFA, nonesterified fatty acid; NFB, nuclear factor B; TNF, tumor necrosis factor

High nonesterified fatty acid (NEFA) concentrations, as observed in the metabolic syndrome, trigger apoptosis of human umbilical vein endothelial cells. Since endothelial apoptosis may contribute to atherothrombosis, we studied the apoptotic susceptibility of human coronary artery endothelial cells (HCAECs) toward selected NEFAs and the underlying mechanisms. HCAECs were treated with single or combined NEFAs. Apoptosis was quantified by flow cytometry, nuclear factor B (NFB) activation by electrophoretic mobility shift assay, and secreted cytokines by enzyme-linked immunosorbent assay. Treatment of HCAECs with saturated NEFAs (palmitate and stearate) increased apoptosis up to fivefold (P < 0.05; n = 4). Unsaturated NEFAs (palmitoleate, oleate, and linoleate) did not promote apoptosis but prevented stearate-induced apoptosis (P < 0.05; n = 4). Saturated NEFA-induced apoptosis neither depended on ceramide formation nor on oxidative NEFA catabolism. However, NEFA activation via acyl-CoA formation was essential. Stearate activated NFB and linoleate impaired stearate-induced NFB activation. Pharmacological inhibition of NFB and inhibitor of B kinase (IKK) also blocked stearate-induced apoptosis. Finally, the saturated NEFA effect on NFB was not attributable to NEFA-induced cytokine production. In conclusion, NEFAs display differential effects on HCAEC survival; saturated NEFAs (palmitate and stearate) are proapoptotic, and unsaturated NEFAs (palmitoleate, oleate, and linoleate) are antilipoapoptotic. Mechanistically, promotion of HCAEC apoptosis by saturated NEFA requires acyl-CoA formation, IKK, and NFB activation.

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