Atorvastatin counteracts high glucose-induced Krüppel-like factor 2 suppression in human umbilical vein endothelial cells.
OBJECTIVE
Krüppel-like factor 2 (KLF2) is a transcription factor that regulates endothelial function and atorvastatin can stabilize atherosclerotic plaque and inhibit inflammation on endothelial cells by attenuating the role of cytokines. The aim of this study is to investigate the effect of high glucose (HG) on KLF2 expression in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms.


METHODS
HUVECs were isolated from the human umbilical cords from normal pregnancies and exposed to medium containing 25.5 mM D-glucose for 24 hours as the HG induction model (HG group). In the HG plus atorvastatin groups or KLF2 gene transduction, the medium then was collected for the nitric oxide (NO) assay and the cells were harvested for Western blot and for the real-time polymerase chain reaction to observe the expression of KLF2, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, total and phosphorylated endothelial NO synthase (eNOS), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, caspase-3 and cleaved caspase-3 and the role of the p38MAPK and ERK1/2 intracellular signal pathway. The cells' apoptosis was analyzed by flow cytometry.


RESULTS
HG dose-dependently increased apoptosis. The presence of HG inhibited the expression of KLF2 mRNA and protein in HUVECs and atorvastatin treatment increased KLF2 expression, thus counteracted HG-induced suppression of KLF2 expression, and overexpression of KLF2 might protect the cells from apoptosis. HG increased the expression of VCAM-1, ICAM-1, but decreased the nitric oxide release and the expression of p-eNOs/eNos in HUVECs. However, atorvastatin reversed these changes and also attenuated high-glucose induced p38 MAPK and ERK1/2 phosphorylation.


CONCLUSIONS
HG suppressed the KLF2 expression in HUVECs. The suppression was counteracted by atorvastatin treatment, probably via attenuating the activation of the signal pathyway p38 MAPK and ERK1/2.
Department of Cardiology, the Second Hospital of Shandong University , Shandong , PR China.
Yu-Sheng
YS
Liu
Dong-Ling
DL
Xu
Zhi-Wei
ZW
Huang
Lin
L
Hao
Xin
X
Wang
Qing-Hua
QH
Lu
D000069059:Atorvastatin; D018929:Cell Culture Techniques; D005947:Glucose / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D011758:Pyrroles; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; D005947:Glucose
Krüppel-like factor 2; atorvastatin; endothelial cells; high glucose; p38 mitogen-activated protein kinase