Superoxide dismutase and catalase inhibit oxidized low-density lipoprotein-induced human aortic smooth muscle cell proliferation: role of cell-cycle regulation, mitogen-activated protein kinases, and transcription factors.
Several antioxidant enzymes, including copper, zinc-superoxide dismutase (Cu, Zn-SOD) and catalase, have been suggested to be protective against the proliferation of vascular smooth muscle cells exposed to oxidative stress. In the present study, we investigated effects of Cu, Zn-SOD and/or catalase on oxLDL-induced proliferation of, and intracellular signaling in, human aortic smooth muscle cells (HASMCs). HASMCs were transfected with adenovirus carrying the human Cu, Zn-SOD gene and/or the human catalase gene. This resulted in a high level of Cu, Zn-SOD and/or catalase overexpression and decreased oxLDL-induced proliferation. Cu, Zn-SOD and/or catalase also arrested cell cycle progression, which was associated with decreased expression of cyclin D1, cyclin E, CDK2, and CDK4 and upregulation of p21(Cip1) and p27(Kip1). Phosphorylation studies on ERK1/2, JNK, and p38, three major subgroups of mitogen activator protein kinases, demonstrated that Cu, Zn-SOD and/or catalase overexpression suppressed ERK1/2 and JNK phosphorylation. Gel-mobility shift analysis showed that oxLDL caused an increase in the DNA binding activity of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), which was inhibited by Cu, Zn-SOD and/or catalase overexpression. These results provide the first evidence that overexpression of Cu, Zn-SOD and/or catalase in HASMCs attenuates the cell proliferation caused by oxLDL stimulation and that this inhibitory effect is mediated via downregulation of ERK1/2 and JNK phosphorylation and AP-1 and NF-kappaB inactivation. These observations support the feasibility of the increase of Cu, Zn-SOD and/or catalase expression in human smooth muscle cells as a means of protection against oxidant injury.
Lin
Shing-Jong
SJ
Institute of Clinical Medicine, National Yang-Ming University, Taiwan, Republic of China.
Shyue
Song-Kun
SK
Shih
Meng-Chun
MC
Chu
Ting-Hui
TH
Chen
Yung-Hsiang
YH
Ku
Hung-Hai
HH
Chen
Jaw-Wen
JW
Tam
Ka-Bik
KB
Chen
Yuh-Lien
YL
D001011:Aorta / Q000166:cytology; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016193:G1 Phase / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; C099252:oxidized low density lipoprotein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3