Document Detail

Differential activation of mitogenic signaling pathways in aortic smooth muscle cells deficient in superoxide dismutase isoforms.
MedLine Citation:
PMID:  15746439     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Reactive oxygen species (ROS) integrate cellular signaling pathways involved in aortic smooth muscle cell (SMC) proliferation and migration associated with atherosclerosis. However, the effect of subcellular localization of ROS on SMC mitogenic signaling is not yet fully understood.
METHODS AND RESULTS: We used superoxide dismutase (SOD)-deficient mouse aortic SMCs to address the role of subcellular ROS localization on SMC phenotype and mitogenic signaling. Compared with wild-type, a 54% decrease in total SOD activity (almost equal to 50% decrease in SOD1 protein levels) and a 42% reduction in SOD2 activity (approximately equal to 50% decrease in SOD2 protein levels) were observed in SOD1+/- and SOD2+/- SMCs, respectively. Consistent with this, basal and thrombin-induced superoxide levels increased in these SMCs. SOD1+/- and SOD2+/- SMCs exhibit increased basal proliferation and enhanced [3H]-thymidine and [3H]-leucine incorporation in basal and thrombin-stimulated conditions. Our results indicate preferential activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinases in SOD1+/- and janus kinase/signal transducer and activator of transcriptase (JAK/STAT) pathway in SOD2+/- SMCs. Pharmacological inhibitors of ERK1/2 p38 and JAK2 confirm the SOD genotype-dependent SMC proliferation.
CONCLUSIONS: Our results suggest that SOD1 and SOD2 regulate SMC quiescence by suppressing divergent mitogenic signaling pathways, and dysregulation of these enzymes under pathophysiological conditions may lead to SMC hyperplasia and hypertrophy.
Nageswara R Madamanchi; Sung-Kwon Moon; Zeenat S Hakim; Shantres Clark; Ali Mehrizi; Cam Patterson; Marschall S Runge
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.     Date:  2005-03-03
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  25     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-05-02     Completed Date:  2005-12-29     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  950-6     Citation Subset:  IM    
Carolina Cardiovascular Biology Center, Department of Medicine, University of North Carolina, Chapel Hill 27599-7005, USA.
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MeSH Terms
Aorta / enzymology,  pathology
Atherosclerosis / metabolism*,  pathology
Cell Compartmentation / physiology
Cell Division / drug effects,  physiology
Cells, Cultured
Enzyme Inhibitors / pharmacology
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors,  metabolism
Gene Expression Regulation, Enzymologic
Janus Kinase 2
MAP Kinase Signaling System / drug effects,  physiology*
Mice, Inbred C57BL
Mice, Mutant Strains
Muscle, Smooth, Vascular / enzymology*,  pathology
Protein-Tyrosine Kinases / antagonists & inhibitors,  metabolism
Proto-Oncogene Proteins / antagonists & inhibitors,  metabolism
Reactive Oxygen Species / metabolism
STAT3 Transcription Factor / metabolism
Superoxide Dismutase / genetics,  metabolism*
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors,  metabolism
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Proto-Oncogene Proteins; 0/Reactive Oxygen Species; 0/STAT3 Transcription Factor; 0/Stat3 protein, mouse; EC 1.15.1.-/superoxide dismutase 1; EC Dismutase; EC dismutase 2; EC Kinase 2; EC Kinases; EC protein, mouse; EC Signal-Regulated MAP Kinases; EC Mitogen-Activated Protein Kinases
Comment In:
Arterioscler Thromb Vasc Biol. 2005 May;25(5):887-8   [PMID:  15863719 ]

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