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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M800393-JLR200 on August 5, 2008

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Journal of Lipid Research, Vol. 49, 2627-2640, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells

Michaela Artwohl1,*, Andrea Lindenmair*, Veronika Sexl{dagger}, Christina Maier*, Georg Rainer§, Angelika Freudenthaler*, Nicole Huttary**, Michael Wolzt*,{dagger}{dagger}, Peter Nowotny*, Anton Luger* and Sabina M. Baumgartner-Parzer*

* Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna A-1090, Austria
{dagger} Institute of Pharmacology, Medical University of Vienna, Vienna A-1090, Austria
§ Department of Ophthalmology, Medical University of Vienna, Vienna A-1090, Austria
** Clinical Institute of Pathology, Medical University of Vienna, Vienna A-1090, Austria
{dagger}{dagger} Department of Clinical Pharmacology, Medical University of Vienna, Vienna A-1090, Austria

Published, JLR Papers in Press, August 5, 2008.

This study was supported by a Charlotte-Bühler grant (H222-B11) from the Austrian Science Fund, Vienna, Austria (M.A.).

1 To whom correspondence should be addressed. e-mail: michaela.artwohl{at}meduniwien.ac.at

Apoptosis and underlying mechanisms were evaluated in human umbilical vein endothelial cells (HUVECs), in target tissues of late diabetic vascular complications [human aortic endothelial cells (HAECs) and human retinal endothelial cells (HRECs)], and in endothelial progenitor cells (EPCs) exposed to FFAs, which are elevated in obesity and diabetes. Saturated stearic acid concentration dependently induced apoptosis that could be mediated via reduced membrane fluidity, because both apoptosis and membrane rigidity are counteracted by eicosapentaenoic acid. PUFAs triggered apoptosis at a concentration of 300 µmol/l in HUVECs, HAECs, and EPCs, but not HRECs, and, in contrast to stearic acid, involved caspase-8 activation. PUFA-induced apoptosis, but not stearic acid-induced apoptosis, strictly correlated (P < 0.01) with protein expression of E2F-1 (r = 0.878) and c-myc (r = 0.966). Lack of c-myc expression and activity owing to quiescence or transfection with dominant negative In373-Myc, respectively, renders HUVECs resistant to PUFA-induced apoptosis. Because c-myc is abundant in growing cells only, apoptosis triggered by PUFAs, but not by saturated stearic acid, obviously depends on the growth/proliferation status of the cells. Finally, this study shows that FFA-induced apoptosis depends on the vascular origin and growth/proliferation status of endothelial cells, and that saturated stearic acid-induced apoptosis and PUFA-induced apoptosis are mediated via different mechanisms.

Supplementary key words aortic endothelial cell • retinal endothelial cell • endothelial progenitor cell • membrane rigidity • caspases • c-myc • E2F-1 • XRCC1 • mad

Abbreviations: DiO, 3,3'-dioctadecyloxacarbocyanine perchlorate; EPA, eicosapentaenoic acid; EPC, endothelial progenitor cell; FCS, fluorescence correlation spectroscopy; HAEC, human aortic endothelial cell; HREC, human retinal endothelial cell; HUVEC, human umbilical vein endothelial cell; XRCC1, X-ray repair cross-complementing 1


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