Adenovirus-mediated overexpression of catalase attenuates oxLDL-induced apoptosis in human aortic endothelial cells via AP-1 and C-Jun N-terminal kinase/extracellular signal-regulated kinase mitogen-activated protein kinase pathways.
In a variety of vascular disorders, endothelial cells (ECs) are exposed to high levels of reactive oxygen species (ROS) generated intercellularly. Recently, several anti-oxidants, including catalase, have been suggested to be cytoprotective against the development of atherosclerosis. The object of this study was to investigate whether adenovirus-mediated gene transfer of catalase in ECs can attenuate ROS production and cell apoptosis under oxidized low density lipoprotein (oxLDL) stimulation. Adenovirus-mediated gene transfer of human catalase gene (Ad-Cat) resulted in a high level of catalase overexpression in human arterial EC (HAEC), which manifested a time-dependent increase in cell viability under the exposure of oxLDL and decreased oxLDL-induced apoptosis. Phosphorylation studies of ERK1/2, JNK, and p38, three subgroups of mitogen activator protein kinase demonstrated that catalase overexpression suppressed JNK phosphorylation and increased ERK1/2 phosphorylation. NF-kappaB and AP-1 were induced after the exposure of HAECs to oxLDL. While catalase overexpression was found to inactivate AP-1, it had no effect on NF-kappaB activity. These results provide the evidence that overexpression of catalase in ECs attenuates ROS production and cell apoptosis under oxLDL stimulation. The protective effect is mediated through the downregulation of JNK and the upregulation of ERK1/2 phosphorylation as well as AP-1 inactivation. This observation supports the feasibility of catalase gene transfer to human endothelium to protect against oxidant injury.
Lin
S-J
SJ
Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan ROC.
Shyue
S-K
SK
Liu
P-L
PL
Chen
Y-H
YH
Ku
H-H
HH
Chen
J-W
JW
Tam
K-B
KB
Chen
Y-L
YL
D000256:Adenoviridae / Q000235:genetics*; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects*; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020869:Gene Expression Profiling; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D008077:Lipoproteins, LDL; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C099252:oxidized low density lipoprotein; D006861:Hydrogen Peroxide; D002374:Catalase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases