title: Altered vascular activation due to deficiency of the NADPH oxidase component p22phox.
abstract: BACKGROUND
  Reactive oxygen species generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase play important roles in vascular activation. The p22(phox) subunit is necessary for the activity of NADPH oxidase complexes utilizing Nox1, Nox2, Nox3, and Nox4 catalytic subunits.
  
  
  METHODS
  We assessed p22(phox)-deficient mice and human tissue for altered vascular activation.
  
  
  RESULTS
  Mice deficient in p22(phox) were smaller than their wild-type littermates but showed no alteration in basal blood pressure. The wild-type littermates were relatively resistant to forming intimal hyperplasia following carotid ligation, and the intimal hyperplasia that developed was not altered by p22(phox) deficiency. However, at the site of carotid artery ligation, the p22(phox)-deficient mice showed significantly less vascular elastic fiber loss compared with their wild-type littermates. This preservation of elastic fibers was associated with a reduced matrix metallopeptidase (MMP) 12/tissue inhibitor of metalloproteinase (TIMP) 1 expression ratio. A similar decrease in the relative MMP12/TIMP1 expression ratio occurred in human coronary artery smooth muscle cells upon knockdown of the hydrogen peroxide responsive kinase CK1αLS. In the ligated carotid arteries, the p22(phox)-deficient mice showed reduced expression of heterogeneous nuclear ribonucleoprotein C (hnRNP-C), suggesting reduced activity of CK1αLS. In a lung biopsy from a human patient with p22(phox) deficiency, there was also reduced vascular hnRNP-C expression.
  
  
  CONCLUSIONS
  These findings indicate that NADPH oxidase complexes modulate aspects of vascular activation including vascular elastic fiber loss, the MMP12/TIMP1 expression ratio, and the expression of hnRNP-C. Furthermore, these findings suggest that the effects of NADPH oxidase on vascular activation are mediated in part by protein kinase CK1αLS.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.forename: Hassan
authors.initials: H
authors.lastname: Albadawi
authors.forename: Zakir
authors.initials: Z
authors.lastname: Siddiquee
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Stone
authors.forename: Mikhail P
authors.initials: MP
authors.lastname: Panchenko
authors.forename: Michael T
authors.initials: MT
authors.lastname: Watkins
authors.forename: James R
authors.initials: JR
authors.lastname: Stone
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000473:pathology; D017536:Carotid Artery, Common / Q000201:enzymology* / Q000473:pathology; D016022:Case-Control Studies; D048128:Casein Kinase Ialpha / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000201:enzymology / Q000473:pathology; D003573:Cytochrome b Group / Q000172:deficiency* / Q000235:genetics; D004547:Elastic Tissue / Q000201:enzymology / Q000473:pathology; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D007223:Infant; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D019255:NADPH Oxidases / Q000172:deficiency* / Q000235:genetics; D058426:Neointima; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014162:Transfection
chemical_list: D003573:Cytochrome b Group; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D017382:Reactive Oxygen Species; C560822:TIMP1 protein, human; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D019255:NADPH Oxidases; C515614:Cyba protein, mouse; D048128:Casein Kinase Ialpha; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12
keywords: HnRNP-C; Hydrogen peroxide; MMP12; MMP3; NADPH oxidase; Protein kinase CK1α; Protein kinase CK1αLS; ROS; Reactive oxygen species; TIMP1; Vascular activation; Vascular injury; heterogeneous nuclear ribonucleoprotein C; hnRNP-C; matrix metallopeptidase 12; matrix metallopeptidase 3; reactive oxygen species; tissue inhibitor of metalloproteinase 1