title: NURR1 involvement in recombinant tissue-type plasminogen activator treatment complications after ischemic stroke.
abstract: OBJECTIVE
  Despite the effectiveness of recombinant tissue-type plasminogen activator (r-tPA) during the acute phase of ischemic stroke, the therapy remains limited by a narrow time window and the occurrence of occasional vascular side effects, particularly symptomatic hemorrhages. Our aim was to investigate the mechanisms underlying the endothelial damage resulting from r-tPA treatment in ischemic-like conditions.
  
  
  METHODS
  Microarray analyses were performed on cerebral endothelial cells submitted to r-tPA treatment during oxygen and glucose deprivation to identify novel biomarker candidates. Validation was then performed in vivo in a mouse model of thromboembolic stroke and culminated in an analysis in a clinical cohort of patients with ischemic stroke treated with thrombolysis.
  
  
  RESULTS
  The transcription factor NURR1 (NR4A2) was identified as a downstream target induced by r-tPA during oxygen and glucose deprivation. Silencing NURR1 expression reversed the endothelial-toxicity induced by the combined stimuli, a protective effect attributable to reduced levels of proinflammatory mediators, such as nuclear factor-kappa-beta 2 (NF-κ-B2), interleukin 1 alpha (IL1α), intercellular adhesion molecule 1 (ICAM1), SMAD family member 3 (SMAD3), colony stimulating factor 2 (granulocyte-macrophage; CSF2). The detrimental effect of delayed thrombolysis, in conditions in which NURR1 gene expression was enhanced, was confirmed in the preclinical stroke model. Finally, we determined that patients with stroke who had a symptomatic hemorrhagic transformation after r-tPA treatment exhibited higher baseline serum NURR1 levels than did patients with an asymptomatic or absence of cerebral bleedings.
  
  
  CONCLUSIONS
  Our results suggest that NURR1 upregulation by r-tPA during ischemic stroke is associated with endothelial dysfunction and inflammation and the enhancement of hemorrhagic complications associated to thrombolysis.
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Cristina
authors.initials: C
authors.lastname: Merino-Zamorano
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.). mar.hernandez.guillamon@vhir.org.
authors.forename: Mar
authors.initials: M
authors.lastname: Hernández-Guillamon
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Amandine
authors.initials: A
authors.lastname: Jullienne
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Béhot
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bardou
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Mireia
authors.initials: M
authors.lastname: Parés
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Israel
authors.initials: I
authors.lastname: Fernández-Cadenas
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Dolors
authors.initials: D
authors.lastname: Giralt
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Caty
authors.initials: C
authors.lastname: Carrera
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Marc
authors.initials: M
authors.lastname: Ribó
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Carine
authors.initials: C
authors.lastname: Ali
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Anna
authors.initials: A
authors.lastname: Rosell
authors.affiliation: From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002545:Brain Ischemia / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D002460:Cell Line; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis; D008297:Male; D051379:Mice; D008875:Middle Aged; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000096:biosynthesis / Q000097:blood*; D020521:Stroke / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D005343:Fibrinolytic Agents; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010959:Tissue Plasminogen Activator
keywords: NURR1; hemorrhagic transformation; stroke; tissue-type plasminogen activator