title: Genetic interleukin-10 deficiency causes vascular remodeling via the upregulation of Nox1.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Jagadeesha K
authors.initials: JK
authors.lastname: Dammanahalli
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Wang
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D002465:Cell Movement; D019332:Endothelin-1 / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology; D017353:Gene Deletion; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000235:genetics*; D034622:RNA Interference; D015854:Up-Regulation
chemical_list: D019332:Endothelin-1; D016753:Interleukin-10; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C000614711:NOX1 protein, mouse; D020780:Matrix Metalloproteinase 9