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. 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 (Ϸ50% decrease in SOD1 protein levels) and a 42% reduction in SOD2 activity (Ϸ50% decrease in SOD2 protein levels) were observed in SOD1 ϩ/Ϫ and SOD2 ϩ/Ϫ SMCs, respectively. Consistent with this, basal and thrombin-induced superoxide levels increased in these SMCs. SOD1ϩ/Ϫ and SOD2 ϩ/Ϫ SMCs exhibit increased basal proliferation and enhanced [3 H]-thymidine and [ 3 H]-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 ϩ/Ϫ and janus kinase/signal transducer and activator of transcriptase (JAK/STAT) pathway in SOD2 ϩ/Ϫ SMCs. Pharmacological inhibitors of ERK1/2 p38 and JAK2 confirm the SOD genotypedependent 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. Key Words: ROS Ⅲ SMC Ⅲ thrombin Ⅲ SOD Ⅲ cell signaling S mooth muscle cells (SMCs) are characterized by marked plasticity in their proliferative potential and differentiation status. As the primary constituents of the arterial media, they provide mechanical support for blood vessels and participate in regulation of vasomotor tone. In addition, SMCs contribute to neointimal formation after vascular injury and during atherosclerotic lesion progression in humans. In advanced atherosclerotic lesions, SMCs are prone to apoptosis and release proteolytic enzymes such as matrix metalloproteinases that may contribute to plaque instability. The remarkable diversity of SMC phenotype and function is determined in large part through regulatory cues in the extracellular microenvironment and interactions among intracellular signaling pathways. In addition, SMC phenotypes are modified over time by the accumulation of injuries to cellular macromolecules. See page 887Reactive oxygen species (ROS) are key components for integration of SMC signaling events, whereas at the same time, they are major contributors to the degradation of cellular function through their interactions with proteins and structural components of the cell. Exogenous ROS are potent stimuli for activation of SMC signaling and mitogenesis, 1 although in high (but physiological) concentrations, they may induce DNA damage and mitochondrial dysfunction. 2 SMCs have several intrinsic mechanisms for generating ROS, the majo...

Reversal of Cardiac Hypertrophy and Fibrosis From Pressure Overload by Tetrahydrobiopterin

“…Restored NOS activity would not itself be expected to stimulate peroxynitrite in the absence of oxidant stress because this is not observed in normal hearts, and if anything, BH4 appears to lower peroxynitrite in oxidant stress disorders. 31 The present data support a growing notion that ROS signaling is compartmentalized 32 and that targeting specific oxidant generators may be more efficacious than broader antioxidant scavengers. Although both Tempol and BH4 provided similar in vitro and tissue (lucigenin) antioxidant effects, their effects on hypertrophy, fibrosis, and NOS dP/dtmax indicates peak rate of pressure rise; Ees, LV end-systolic elastance (stiffness); V100, end-systolic volume at end-systolic pressure of 100 mm Hg; M SW, slope of stroke work-end-diastolic volume relationship; dP/dtmin, peak rate of pressure decline; (norm), time constant of relaxation normalized to heart rate; and PFR/EDV, peak filling rate normalized to end-diastolic volume.…”

Enhanced Expression of Janus Kinase–Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy

“…Enhanced production of ROS has been described as a potential major activator of Jak/Stat signaling (33) and can occur independently of the addition of exogenous cytokines (34). This phenomenon appears to be relatively general since ROS mediate induction of Jak-2 activation in tissues such as cardiac myocytes and vascular smooth muscle cells (34 -36) as well as kidney cells (12,14,15,32).…”

Comparative effects of pitavastatin and probucol on oxidative stress, Cu/Zn superoxide dismutase, PPAR-γ, and aortic stiffness in hypercholesterolemia

“…PPAR-␥ activators may promote the regression of fatty streaks by increasing the removal of cholesterol from macrophages (29), and they may also prevent vascular remodeling (19). Furthermore, Madamanchi et al (27) reported that Cu/ZnSOD may be involved in vascular smooth muscle cell hyperplasia and hypertrophy. These data support our observation that pitavastatin may inhibit fatty streak formation and vascular remodeling more than probucol via the activation of PPAR-␥; it also appears that pitavastatin may reduce ROS by restoring Cu/ZnSOD activity in the vascular wall in cholesterol-fed rabbits.…”