BACKGROUND AND HYPOTHESIS: Interleukin (IL)-10 is an anti-inflammatory cytokine. Nox1 is a mitogenic oxidase (p65-mox). The objective of this study was to test a hypothesis that IL-10 deficiency would cause vascular remodeling via the upregulation of Nox1. METHODS AND RESULTS: Recombinant adeno-associated virus (AAV) carrying short hairpin small interference RNA for Nox1 (AAV.Nox1shRNA) was constructed for in-vivo-specific inhibition of Nox1. Three groups of IL-10 gene knockout (IL-10KO) mice and three groups of wild-type mice were used. Three groups of each strain received intravenous delivery of AAV.Nox1shRNA, AAV with scrambled shRNA, and PBS, respectively. Animals were euthanized at 3 weeks after gene delivery. IL-10KO increased Nox1 protein expression, NADPH oxidase activity, and superoxide production in aortas. IL-10KO also resulted in a significant decrease in aortic medial thickness, a loss of smooth muscle cells (SMCs), and an increase in vascular collagen deposition, indicating vascular remodeling. The IL-10KO induced increases in NADPH oxidase activity and superoxide production, and vascular remodeling were abolished by silencing of Nox1 (p65-mox), suggesting that these effects may be mediated by the upregulation of Nox1. In addition, IL-10KO increased endothelin-1 levels in plasma and aortas, and this effect was partially blocked by silencing of Nox1. RNA interference silencing of Nox1 obliterated the IL-10KO-induced increases in IL-6 expression in aortas, superoxide production, and matrix metalloproteinase-9 activity in aortic SMCs, and SMC migration. CONCLUSION: IL-10 is essential for the maintenance of normal vasculature, as IL-10 deficiency resulted in vascular damage and remodeling. The IL-10KO-induced vascular structure damage may be mediated by the upregulation of Nox1.
BACKGROUND AND HYPOTHESIS: Interleukin (IL)-10 is an anti-inflammatory cytokine. Nox1 is a mitogenic oxidase (p65-mox). The objective of this study was to test a hypothesis that IL-10 deficiency would cause vascular remodeling via the upregulation of Nox1. METHODS AND RESULTS: Recombinant adeno-associated virus (AAV) carrying short hairpin small interference RNA for Nox1 (AAV.Nox1shRNA) was constructed for in-vivo-specific inhibition of Nox1. Three groups of IL-10 gene knockout (IL-10KO) mice and three groups of wild-type mice were used. Three groups of each strain received intravenous delivery of AAV.Nox1shRNA, AAV with scrambled shRNA, and PBS, respectively. Animals were euthanized at 3 weeks after gene delivery. IL-10KO increased Nox1 protein expression, NADPH oxidase activity, and superoxide production in aortas. IL-10KO also resulted in a significant decrease in aortic medial thickness, a loss of smooth muscle cells (SMCs), and an increase in vascular collagen deposition, indicating vascular remodeling. The IL-10KO induced increases in NADPH oxidase activity and superoxide production, and vascular remodeling were abolished by silencing of Nox1 (p65-mox), suggesting that these effects may be mediated by the upregulation of Nox1. In addition, IL-10KO increased endothelin-1 levels in plasma and aortas, and this effect was partially blocked by silencing of Nox1. RNA interference silencing of Nox1 obliterated the IL-10KO-induced increases in IL-6 expression in aortas, superoxide production, and matrix metalloproteinase-9 activity in aortic SMCs, and SMC migration. CONCLUSION:IL-10 is essential for the maintenance of normal vasculature, as IL-10 deficiency resulted in vascular damage and remodeling. The IL-10KO-induced vascular structure damage may be mediated by the upregulation of Nox1.
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