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HuR mediates the synergistic effects of angiotensin II and IL ‐1β on vascular COX ‐2 expression and cell migration
Author(s) -
Aguado A,
Rodríguez C,
MartínezRevelles S,
Avendaño M S,
Zhenyukh O,
Orriols M,
MartínezGonzález J,
Alonso M J,
Briones A M,
Dixon D A,
Salaices M
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13103
Subject(s) - angiotensin ii , vascular smooth muscle , western blot , cell migration , chemistry , receptor , microbiology and biotechnology , biology , endocrinology , cell , biochemistry , smooth muscle , gene
Background and Purpose 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 m RNA 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. Experimental Approach Rat and human VSMCs were stimulated with AngII (0.1 μ M ) and/or IL ‐1β (10 ng·m L −1 ). Mice were infused with AngII or subjected to carotid artery ligation. m RNA and protein levels were assayed by quantitative PCR , W estern blot, immunohistochemistry and immunofluorescence. Cell migration was measured by wound healing and transwell assays. Key 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 m RNA stability, mediated through cytoplasmic HuR translocation and COX ‐2 m RNA binding. These effects were blocked by ERK 1/2 and HuR inhibitors. VSMC migration was reduced by blockade of ERK 1/2, HuR , COX ‐2, TXAS , TP and EP receptors. HuR , COX ‐2, m PGES ‐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 m PGES ‐1 deletion. Conclusions and Implications The synergistic induction of COX ‐2 by AngII and IL ‐1β in VSMCs involves HuR through an ERK 1/2‐dependent mechanism. The HuR / COX ‐2 axis participates in cell migration and vascular damage. HuR might be a novel target to modulate vascular remodelling.