Involvement of glycogen synthase kinase-3beta in palmitate-induced human umbilical vein endothelial cell apoptosis.
OBJECTIVE
The death of endothelial cells may play a critical role in the development of various vascular diseases, including atherosclerosis. While free fatty acids (FFAs) may stimulate endothelial apoptosis, the molecular and cellular mechanisms of this effect have not been studied intensively. To elucidate the mechanisms involved in FFA-induced endothelial cell apoptosis, we investigated the effect of different pharmacological inhibitors on palmitate-induced apoptosis in human umbilical vein endothelial cells (HUVECs). Interestingly, lithium, a glycogen synthase kinase-3 (GSK-3) inhibitor, showed a strong protective effect.


RESULTS
To examine the involvement of GSK-3beta in palmitate-induced HUVEC apoptosis, its dephosphorylation at Ser9 and enzymatic activation in response to palmitate treatment were monitored by immunoblotting and in vitro kinase assays, respectively. GSK-3beta was dephosphorylated and its enzymatic activity increased in palmitate-treated HUVECs. In addition, pretreatment with other GSK-3beta inhibitors, e.g. SB216763 or TDZD-8, as well as adenoviral transduction with a catalytically inactive GSK-3beta had significant protective effects against palmitate-induced HUVEC apoptosis.


CONCLUSIONS
These results demonstrate that the GSK-3beta signalling pathway is involved in palmitate-induced HUVEC apoptosis.
Choi
Sung-E
SE
Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea.
Kang
Yup
Y
Jang
Hyun-Ju
HJ
Shin
Ha-Chul
HC
Kim
Hyo-Eun
HE
Kim
Hyo-Soo
HS
Kim
Hae Jin
HJ
Kim
Dae Jung
DJ
Lee
Kwan-Woo
KW
D000256:Adenoviridae / Q000235:genetics; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D003600:Cytosol / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology*; D004789:Enzyme Activation / Q000187:drug effects; D037341:Fumonisins / Q000494:pharmacology; D005822:Genetic Vectors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008928:Mitochondria / Q000737:chemistry; D010168:Palmitates / Q000494:pharmacology*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology; D014161:Transduction, Genetic; D014471:Umbilical Veins
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000873:Anthracenes; D037341:Fumonisins; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D010168:Palmitates; D011725:Pyridines; C417521:SB 216763; D013830:Thiadiazoles; D010768:Phosphoserine; C432165:pyrazolanthrone; C056933:fumonisin B1; D011065:Poly(ADP-ribose) Polymerases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D018021:Lithium Chloride; C070515:bisindolylmaleimide I; C093642:SB 203580