title: The flavo-oxidase QSOX1 supports vascular smooth muscle cell migration and proliferation: Evidence for a role in neointima growth.
abstract: Quiescin sulfhydryl oxidase 1 (QSOX1) is a flavoenzyme largely present in the extracellular milieu whose physiological functions and substrates are not known. QSOX1 has been implicated in the regulation of tumor cell survival, proliferation and migration, in addition to extracellular matrix (ECM) remodeling. However, data regarding other pathophysiological conditions are still lacking. Arterial injury by balloon catheter is an established model of post-angioplasty restenosis. This technique induces neointima formation due to migration and proliferation of vascular smooth muscle cells (VSMC), followed by ECM synthesis and remodeling. Here, we show that QSOX1 knockdown inhibited VSMC migration and proliferation in vitro. In contrast, QSOX1 overexpression stimulated these processes. While migration could be induced by the incubation of cells with the active recombinant QSOX1, proliferation was induced by addition of the active and also of an inactive mutant QSOX1 protein. The proliferation induced by both recombinants was independent of intracellular hydrogen peroxide and dependent of the MEK/ERK pathway. To recapitulate in vivo VSMC pathophysiology, balloon-induced arterial injury was performed. The expression of QSOX1 in the neointimal layer of balloon-injured rat carotids was high and peaked at 14 days post-injury. In vivo QSOX1 knockdown led to a significant decrease in PCNA expression at day 14 post-injury and a decreased intima/media area ratio at day 21 post-injury, compared with scrambled siRNA transfection. In summary, our findings demonstrate that QSOX1 induces VSMC migration and proliferation in vitro and contributes to neointima thickening in balloon-injured rat carotids.
authors.affiliation: Departamento de Patologia Básica, Universidade Federal do Paraná, Centro Politécnico, Curitiba 81531-980, Brazil.
authors.forename: Beatriz E
authors.initials: BE
authors.lastname: Borges
authors.affiliation: Departamento de Patologia Básica, Universidade Federal do Paraná, Centro Politécnico, Curitiba 81531-980, Brazil.
authors.forename: Márcia H
authors.initials: MH
authors.lastname: Appel
authors.affiliation: Departamento de Patologia Básica, Universidade Federal do Paraná, Centro Politécnico, Curitiba 81531-980, Brazil.
authors.forename: Axel R
authors.initials: AR
authors.lastname: Cofré
authors.affiliation: Departamento de Patologia Básica, Universidade Federal do Paraná, Centro Politécnico, Curitiba 81531-980, Brazil.
authors.forename: Maiara L
authors.initials: ML
authors.lastname: Prado
authors.affiliation: Departamento de Patologia Básica, Universidade Federal do Paraná, Centro Politécnico, Curitiba 81531-980, Brazil.
authors.forename: Chelin A
authors.initials: CA
authors.lastname: Steclan
authors.affiliation: INSERM UMR 1100, Université François Rabelais F-37032 Tours, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Esnard
authors.affiliation: Departamento de Patologia Básica, Universidade Federal do Paraná, Centro Politécnico, Curitiba 81531-980, Brazil.
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Zanata
authors.affiliation: Laboratório de Biologia Vascular, Heart Institute, Universidade de São Paulo, São Paulo 05403-900, Brazil.
authors.forename: Francisco R M
authors.initials: FR
authors.lastname: Laurindo
authors.affiliation: Departamento de Patologia Básica, Universidade Federal do Paraná, Centro Politécnico, Curitiba 81531-980, Brazil. Electronic address: lia.nakao@ufpr.br.
authors.forename: Lia S
authors.initials: LS
authors.lastname: Nakao
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000473:pathology / Q000601:surgery; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology; D058426:Neointima / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D013879:Thioredoxins; D006861:Hydrogen Peroxide; C525178:quiescin Q6 sulfhydyl oxidase 1, rat
keywords: Cell migration; Cell proliferation; Neointima; Quiescin sulfhydryl oxidase; Vascular smooth muscle cell