title: Glutathione peroxidase-deficient smooth muscle cells cause paracrine activation of normal smooth muscle cells via cyclophilin A.
abstract: OBJECTIVE
  Reduced activity of the antioxidant glutathione peroxidase-1 (GPx1) correlates with increased risk of cardiovascular events in patients with coronary artery disease. However, it remains unclear whether this imbalance in antioxidant capacity directly contributes to activation of vascular cells. In response to oxidative stress, smooth muscle cells (SMCs) secrete the pro-inflammatory immunomodulator cyclophilin A (CyPA). We hypothesized that reduction in vascular cell GPx1 activity causes secretion of CyPA and paracrine-mediated activation of NF-κB and proliferation of SMCs.
  
  
  RESULTS
  Using a murine model of GPx1 deficiency (GPx1(+/-)), we found elevated levels of hydrogen peroxide levels and increased secretion of CyPA in both arterial segments and cultured SMCs as compared to wild type (WT). Conditioned media from GPx1(+/-) SMCs caused increased NF-κB activation of quiescent WT SMCs, and this was inhibited by the antioxidant N-acetyl-l-cysteine or by cyclosporine A (CsA). In co-culture experiments, SMCs derived from GPx1(+/-) aorta caused increased proliferation of WT SMCs, which was also inhibited by CsA.
  
  
  CONCLUSIONS
  Reduction in vascular cell GPx1 activity and the associated increase in oxidative stress cause CyPA-mediated paracrine activation of SMCs. These findings identify a novel mechanism by which an imbalance in antioxidant capacity may contribute to vascular disease.
authors.affiliation: Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Maysam
authors.initials: M
authors.lastname: Takapoo
authors.forename: Ali H
authors.initials: AH
authors.lastname: Chamseddine
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Bhalla
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Miller
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002339:Carotid Arteries / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003433:Crosses, Genetic; D017077:Culture Media, Conditioned / Q000378:metabolism; D021984:Cyclophilin A / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D017077:Culture Media, Conditioned; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D021984:Cyclophilin A; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse