HuR mediates the synergistic effects of angiotensin II and IL-1 on vascular COX-2 expression and cell migration
Por:
Aguado, A, Rodriguez, C, Martinez-Revelles, S, Avendano, MS, Zhenyukh, O, Orriols, M, Martinez-Gonzalez, J, Alonso, MJ, Briones, AM, Dixon, DA, Salaices, M
Publicada:
1 jun 2015
Resumen:
Background and PurposeAngiotensin II (AngII) and IL-1 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-1 and its consequences on VSMC migration and remodelling.
Experimental ApproachRat and human VSMCs were stimulated with AngII (0.1M) and/or IL-1 (10ngmL(-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.
Key ResultsIn VSMCs, AngII potentiated COX-2 and tenascin-C expressions and cell migration induced by IL-1. This effect of AngII on IL-1-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 and ImplicationsThe synergistic induction of COX-2 by AngII and IL-1 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.
Filiaciones:
Aguado, A:
Univ Autonoma Madrid, Dept Farmacol, Inst Invest Hosp La Paz IdiPAZ, Madrid 28029, Spain
Rodriguez, C:
IIB St Pau, Ctr Invest Cardiovasc CSIC ICCC, Barcelona, Spain
Martinez-Revelles, S:
Univ Autonoma Madrid, Dept Farmacol, Inst Invest Hosp La Paz IdiPAZ, Madrid 28029, Spain
Avendano, MS:
Univ Autonoma Madrid, Dept Farmacol, Inst Invest Hosp La Paz IdiPAZ, Madrid 28029, Spain
Zhenyukh, O:
Univ Autonoma Madrid, Dept Farmacol, Inst Invest Hosp La Paz IdiPAZ, Madrid 28029, Spain
Orriols, M:
IIB St Pau, Ctr Invest Cardiovasc CSIC ICCC, Barcelona, Spain
Martinez-Gonzalez, J:
IIB St Pau, Ctr Invest Cardiovasc CSIC ICCC, Barcelona, Spain
Alonso, MJ:
Univ Rey Juan Carlos, Dept Ciencias Basicas Salud, Alcorcon, Spain
Briones, AM:
Univ Autonoma Madrid, Dept Farmacol, Inst Invest Hosp La Paz IdiPAZ, Madrid 28029, Spain
Dixon, DA:
Univ Kansas, Med Ctr, Dept Canc Biol, Kansas City, KS 66160 USA
Salaices, M:
Univ Autonoma Madrid, Dept Farmacol, Inst Invest Hosp La Paz IdiPAZ, Madrid 28029, Spain
Green Published, Bronze
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