title: HuR mediates the synergistic effects of angiotensin II and IL-1β on vascular COX-2 expression and cell migration.
abstract: OBJECTIVE
  Angiotensin II (AngII) and IL-1β are involved in cardiovascular diseases through the induction of inflammatory pathways. HuR is an adenylate- and uridylate-rich element (ARE)-binding protein involved in the mRNA stabilization of many genes. This study investigated the contribution of HuR to the increased expression of COX-2 induced by AngII and IL-1β and its consequences on VSMC migration and remodelling.
  
  
  METHODS
  Rat and human VSMCs were stimulated with AngII (0.1 μM) and/or IL-1β (10 ng · mL(-1)). Mice were infused with AngII or subjected to carotid artery ligation. mRNA and protein levels were assayed by quantitative PCR, Western blot, immunohistochemistry and immunofluorescence. Cell migration was measured by wound healing and transwell assays.
  
  
  RESULTS
  In VSMCs, AngII potentiated COX-2 and tenascin-C expressions and cell migration induced by IL-1β. This effect of AngII on IL-1β-induced COX-2 expression was accompanied by increased COX-2 3' untranslated region reporter activity and mRNA stability, mediated through cytoplasmic HuR translocation and COX-2 mRNA binding. These effects were blocked by ERK1/2 and HuR inhibitors. VSMC migration was reduced by blockade of ERK1/2, HuR, COX-2, TXAS, TP and EP receptors. HuR, COX-2, mPGES-1 and TXAS expressions were increased in AngII-infused mouse aortas and in carotid-ligated arteries. AngII-induced tenascin-C expression and vascular remodelling were abolished by celecoxib and by mPGES-1 deletion.
  
  
  CONCLUSIONS
  The synergistic induction of COX-2 by AngII and IL-1β in VSMCs involves HuR through an ERK1/2-dependent mechanism. The HuR/COX-2 axis participates in cell migration and vascular damage. HuR might be a novel target to modulate vascular remodelling.
authors: Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz (IdiPAZ), Madrid, Spain.
authors: A
authors: A
authors: Aguado
authors: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors: C
authors: C
authors: Rodríguez
authors: Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz (IdiPAZ), Madrid, Spain.
authors: S
authors: S
authors: Martínez-Revelles
authors: Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz (IdiPAZ), Madrid, Spain.
authors: M S
authors: MS
authors: Avendaño
authors: Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz (IdiPAZ), Madrid, Spain.
authors: O
authors: O
authors: Zhenyukh
authors: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors: M
authors: M
authors: Orriols
authors: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors: J
authors: J
authors: Martínez-González
authors: Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.
authors: M J
authors: MJ
authors: Alonso
authors: Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz (IdiPAZ), Madrid, Spain.
authors: A M
authors: AM
authors: Briones
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: D A
authors: DA
authors: Dixon
authors: Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz (IdiPAZ), Madrid, Spain.
authors: M
authors: M
authors: Salaices
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D000068579:Celecoxib / Q000494:pharmacology; D002465:Cell Movement / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004357:Drug Synergism; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019063:Tenascin / Q000235:genetics; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D000067780:ELAV-Like Protein 1; D053583:Interleukin-1beta; D012333:RNA, Messenger; D019063:Tenascin; D000804:Angiotensin II; D051546:Cyclooxygenase 2; D000068579:Celecoxib
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