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Abstract
The mitochondrial antioxidant manganese superoxide dismutase (Mn-SOD) plays a critical cytoprotective role against oxidative stress. Vascular endothelial growth factor (VEGF) was shown previously to induce expression of Mn-SOD in endothelial cells by a NADPH oxidase-dependent mechanism. The goal of the current study was to determine the transcriptional mechanisms underlying this phenomenon. VEGF resulted in protein kinase C-dependent phosphorylation of IkappaB and subsequent translocation of p65 NF-kappaB into the nucleus. Overexpression of constitutively active IkappaB blocked VEGF stimulation of Mn-SOD. In transient transfection assays, VEGF increased Mn-SOD promoter activity, an effect that was dependent on a second intronic NF-kappaB consensus motif. In contrast, VEGF-mediated induction of Mn-SOD was enhanced by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and by dominant negative Akt and was decreased by constitutively active Akt. Overexpression of a constitutively active (phosphorylation-resistant) form of FKHRL1 (TMFKHRL1) resulted in increased Mn-SOD expression, suggesting that the negative effect of PI3K-Akt involves attenuation of forkhead activity. In co-transfection assays, the Mn-SOD promoter was transactivated by TMFKHRL1. Flavoenzyme inhibitor, diphenyleneiodonium (DPI), and antisense oligonucleotides against p47phox (AS-p47phox) inhibited VEGF stimulation of IkappaB/NF-kappaB and forkhead phosphorylation, supporting a role for NADPH oxidase activity in both signaling pathways. Like VEGF, hepatocyte growth factor (HGF) activated the PI3K-Akt-forkhead pathway. However, HGF-PI3K-Akt-forkhead signaling was insensitive to diphenyleneiodonium and AS-p47phox. Moreover, HGF failed to induce phosphorylation of IkappaB/NF-kappaB or nuclear translocation of NF-kappaB and had no effect on Mn-SOD expression. Together, these data suggest that VEGF is uniquely coupled to Mn-SOD expression through growth factor-specific reactive oxygen species (ROS)-sensitive positive (protein kinase C-NF-kappaB) and negative (PI3K-Akt-forkhead) signaling pathways.
Highlights
VEGF1 is an endothelial cell-specific mitogen and chemotactic agent that is involved in wound repair, angiogenesis of ischemic tissue, tumor growth, microvascular permeability, vascular protection, and hemostasis
Vascular endothelial growth factor (VEGF)-mediated Induction of manganese superoxide dismutase (Mn-SOD) Is Attenuated by the phosphatidylinositol 3-kinase (PI3K)-Akt-Forkhead Signaling Pathway—Previous studies in non-endothelial cells have demonstrated that insulin inhibits Mn-SOD expression via a PI3K-Akt-forkhead-dependent pathway [31]
HCAEC and human umbilical vein endothelial cells (HUVEC) were preincubated for 30 min in the absence or presence of the PI3K inhibitor LY294002 (50 M) or wortmannin (100 nM), treated with VEGF (50 ng/ml) for 4 h, and processed for Northern blot analysis of Mn-SOD
Summary
VEGF1 is an endothelial cell-specific mitogen and chemotactic agent that is involved in wound repair, angiogenesis of ischemic tissue, tumor growth, microvascular permeability, vascular protection, and hemostasis (for review, see Refs. 1–3). VEGF1 is an endothelial cell-specific mitogen and chemotactic agent that is involved in wound repair, angiogenesis of ischemic tissue, tumor growth, microvascular permeability, vascular protection, and hemostasis Of the VEGF receptors, KDR/Flk-1 is believed to play the most important role in mediating endothelial cell proliferation, migration, and permeability. We demonstrated that VEGF induces the activity of NADPH oxidase and that NADPH oxidase-derived reactive oxygen species (ROS) are, in turn, required for VEGF-mediated induction of cell migration, proliferation, and manganese superoxide dismutase (Mn-SOD) expression. Redox Regulation of Forkhead and IB/NF-B by VEGF encoded by the nuclear SOD2 gene and is localized in mitochondria, the major site for oxidative phosphorylation. ROS have been shown to induce mitochondrial damage and dysfunction, leading to an impaired Krebs’ cycle and induction of apoptotic pathways Overexpression of Mn-SOD in transgenic mice protects against oxidative injuries caused by ischemia-reperfusion in the brain, oxygen therapy-induced inflammation in the lungs, and drug-induced toxicity in the heart (24 –26)
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