NURR1 involvement in recombinant tissue-type plasminogen activator treatment complications after ischemic stroke

Stroke. 2015 Feb;46(2):477-84. doi: 10.1161/STROKEAHA.114.006826. Epub 2014 Dec 11.


Background and purpose: 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.

Keywords: NURR1; hemorrhagic transformation; stroke; tissue-type plasminogen activator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Biomarkers / blood
  • Brain Ischemia / blood*
  • Brain Ischemia / diagnosis
  • Brain Ischemia / drug therapy*
  • Cell Line
  • Female
  • Fibrinolytic Agents / adverse effects
  • Fibrinolytic Agents / therapeutic use
  • Humans
  • Inflammation / blood
  • Inflammation / chemically induced
  • Inflammation / diagnosis
  • Male
  • Mice
  • Middle Aged
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / biosynthesis
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / blood*
  • Stroke / blood*
  • Stroke / diagnosis
  • Stroke / drug therapy*
  • Tissue Plasminogen Activator / adverse effects
  • Tissue Plasminogen Activator / therapeutic use*
  • Treatment Outcome


  • Biomarkers
  • Fibrinolytic Agents
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Tissue Plasminogen Activator