Journal Article

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

Cora Weigert, Hans-Ulrich Häring, Monika Kellerer, Katrin Staiger, Harald Staiger, Carina Haas

2006

Overview

Saturated, but Not Unsaturated, Fatty Acids Induce Apoptosis of Human Coronary Artery Endothelial Cells via Nuclear Factor-κB Activation Katrin Staiger 1 , Harald Staiger 1 , Cora Weigert 1 , Carina Haas 1 , Hans-Ulrich Häring 1 and Monika Kellerer 1 2 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 Abstract 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 κB (NFκB) 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 NFκB and linoleate impaired stearate-induced NFκB activation. Pharmacological inhibition of NFκB and inhibitor of κB kinase (IKK) also blocked stearate-induced apoptosis. Finally, the saturated NEFA effect on NFκB 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 NFκB activation. HCAEC, human coronary artery endothelial cell HUVEC, human umbilical vein endothelial cell IKK, inhibitor of κB kinase IL, interleukin NEFA, nonesterified fatty acid NFκB, nuclear factor κB TNF, tumor necrosis factor Footnotes K.S. and H.S. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 15, 2006. Received February 9, 2006. DIABETES

• Publisher: American Diabetes Association
• Subject: Apoptosis / Biological and medical sciences / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Endothelial growth factors / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Fatty acids / Health aspects / Medical sciences