HuR mediates the synergistic effects of angiotensin II and IL-1β on vascular COX-2 expression and cell migration

Abstract

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.