title: Differential activation of mitogenic signaling pathways in aortic smooth muscle cells deficient in superoxide dismutase isoforms.
abstract: 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.
  
  
  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.
authors.affiliation: Carolina Cardiovascular Biology Center, Department of Medicine, University of North Carolina, Chapel Hill 27599-7005, USA.
authors.forename: Nageswara R
authors.initials: NR
authors.lastname: Madamanchi
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
authors.forename: Zeenat S
authors.initials: ZS
authors.lastname: Hakim
authors.forename: Shantres
authors.initials: S
authors.lastname: Clark
authors.forename: Ali
authors.initials: A
authors.lastname: Mehrizi
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Marschall S
authors.initials: MS
authors.lastname: Runge
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002451:Cell Compartmentation / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006984:Hypertrophy; D053614:Janus Kinase 2; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D053614:Janus Kinase 2; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D048051:p38 Mitogen-Activated Protein Kinases; D000099156:Superoxide Dismutase 2; C494087:Stat3 protein, mouse; C000606291:Sod1 protein, mouse; C507926:Jak2 protein, mouse