Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells.
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 micromol/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.
Artwohl
Michaela
M
Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna A-1090, Austria. michaela.artwohl@meduniwien.ac.at
Lindenmair
Andrea
A
Sexl
Veronika
V
Maier
Christina
C
Rainer
Georg
G
Freudenthaler
Angelika
A
Huttary
Nicole
N
Wolzt
Michael
M
Nowotny
Peter
P
Luger
Anton
A
Baumgartner-Parzer
Sabina M
SM
D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005227:Fatty Acids / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1
D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D000076105:X-ray Repair Cross Complementing Protein 1; D053181:Caspase 8