Published online before print March 3, 2005, doi: 10.1161/01.ATV.0000161050.77646.68
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© 2005 American Heart Association, Inc.
Vascular Biology |
Differential Activation of Mitogenic Signaling Pathways in Aortic Smooth Muscle Cells Deficient in Superoxide Dismutase Isoforms
From the Carolina Cardiovascular Biology Center (N.R.M., Z.S.H., S.C., M.A., C.P., M.S.R.), Department of Medicine, University of North Carolina, Chapel Hill; and the Department of Food and Biotechnology (S.-K.M.), Chungju National University, Chungju City, Chungbuk, Republic of Korea.
Correspondence to Marschall S. Runge, Department of Medicine, University of North Carolina at Chapel Hill, 3033 Old Clinic Building, Chapel Hill, NC 27599-7005. E-mail mrunge{at}med.unc.edu
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 (
50% decrease in SOD1 protein levels) and a 42% reduction in SOD2 activity (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.
We investigated the effect of subcellular reactive oxygen species (ROS) localization on smooth muscle cell (SMC) phenotype and mitogenic signaling using superoxide dismutase (SOD)–deficient mouse aortic SMCs. ROS location modulates SMC phenotype via divergent signaling pathways, and dysregulation of SOD under pathophysiological conditions may lead to SMC hyperplasia and hypertrophy.
Key Words: ROS • SMC • thrombin • SOD • cell signaling
Related Article:
Arterioscler Thromb Vasc Biol 2005 25: 887-888.
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