title: Nitric oxide inhibits neointimal hyperplasia following vascular injury via differential, cell-specific modulation of SOD-1 in the arterial wall.
abstract: Superoxide (O2(•-)) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide ((•)NO) inhibits neointimal hyperplasia through various cell-specific mechanisms, including redox regulation. What remains unclear is whether (•)NO exerts cell-specific regulation of the vascular redox environment following arterial injury to inhibit neointimal hyperplasia. Therefore, the aim of the present study was to assess whether (•)NO exerts cell-specific, differential modulation of O2(•-) levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates (•)NO-dependent inhibition of neointimal hyperplasia. In vivo, (•)NO increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro, (•)NO increased SOD-1 levels in vascular smooth muscle cells (VSMC), but had no effect on SOD-1 in endothelial cells or adventitial fibroblasts. This SOD-1 increase was associated with an increase in sod1 gene expression, increase in SOD-1 activity, and decrease in O2(•-) levels. Lastly, to determine the role of SOD-1 in (•)NO-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (KO) mice, with and without (•)NO. Interestingly, (•)NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 KO mice. In conclusion, these data show the cell-specific modulation of O2(•-) by (•)NO through regulation of SOD-1 in the vasculature, highlighting its importance on the inhibition of neointimal hyperplasia. These results also shed light into the mechanism of (•)NO-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia.
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA.
authors.forename: Edward S M
authors.initials: ES
authors.lastname: Bahnson
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Koo
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Nadiezhda
authors.initials: N
authors.lastname: Cantu-Medellin
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA.
authors.forename: Aaron Y
authors.initials: AY
authors.lastname: Tsui
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Havelka
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Vercammen
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Kelley
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA. Electronic address: mkibbe@nmh.org.
authors.forename: Melina R
authors.initials: MR
authors.lastname: Kibbe
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D058426:Neointima / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D009569:Nitric Oxide; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Neointimal hyperplasia; Nitric oxide; SOD1; Superoxide; Vascular