HuR mediates the synergistic effects of angiotensin II and IL-1β on vascular COX-2 expression and cell migration
EntityUAM. Departamento de Farmacología; Instituto de Investigación Sanitaria del Hospital Universitario de La Paz (IdiPAZ); Centro de Investigación Cardiovascular (CIC)
PublisherThe British Pharmacological Society
10.1111/bph.13103British Journal of Phamacoly 172.12 (20125): 3028-42
ISSN0007-1188 (print); 1476-5381 (on line)
Funded byThis study was supported by MINECO (SAF2012-36400 and SAF2012-40127), ISCIII (RD12/0042/0024, RD12/0042/0053, PI13/01488), Fundación Mutua Madrileña, UAM-Grupo Santander and NIH (R01CA134609). AA and AMB were supported by a FPI fellowship and the Ramón y Cajal program (RYC-2010-06473), respectively
ProjectGobierno de España. SAF2012-36400; Gobierno de España. SAF2012-40127
SubjectsCell migration; Cytokines; Inflammatory mediators; Smooth muscle cells; Vascular remodeling; Farmacia
NoteThis is the peer-reviewed version of the following article: HuR mediates the synergistic effects of angiotensin II and IL-1β on vascular COX-2 expression and cell migration, British Journal of Pharmacology 172.12 (2015): 3028-3042 , which has been published in final form at http://dx.doi.org/10.1111/bph.13103. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-Archiving
Rights© 2015 The British Pharmacological Society.
BACKGROUND AND PURPOSE: Angiotensin II (AngII) and interleukin 1β (IL-1β) are involved in cardiovascular diseases through induction of inflammatory pathways. HuR is an ARE-binding protein that contributes to the mRNA stabilization of many genes. This study investigated the contribution of HuR upon COX-2 expression induced by AngII and IL-1β and its consequences on vascular smooth muscle cell (VSMC) migration and remodeling. EXPERIMENTAL APPROACH: Rat and human VSMC stimulated with AngII (0.1 μM) and/or IL-1β (10 ng·mL-1 ) and mice infused with AngII or subjected to carotid artery ligation were used. mRNA and protein levels were assayed by qPCR, western blot, immunohistochemistry, and immunofluorescence. Cell migration was measured by wound healing and transwell assays. KEY RESULTS: In VSMC, AngII potentiated COX-2 and tenascin-C expressions and cell migration induced by IL-1β. The effect of AngII on IL-1β-induced COX-2 expression was accompanied by increased COX-2 3'UTR reporter activity and mRNA stability occurring 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 remodeling were abolished by celecoxib and by mPGES-1 deletion. CONCLUSIONS AND IMPLICATIONS: The synergistic induction of COX-2 by AngII and IL-1β in VSMC 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 remodeling.
Google Scholar:Aguado Gómez, Alfredo - Rodríguez, C. - Martínez-Revelles, Sonia - Avendaño, M. S. - Zhenyukh, O. - Orriols, M. - Martínez-González, J. - Alonso, M. J. - Briones Alonso, Ana María - Dixon, D. A. - Salaices Sánchez, Mercedes
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