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

Abstract

BACKGROUND AND PURPOSEAngiotensin 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. EXPERIMENTAL APPROACHRat 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. KEY RESULTSIn 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.

The many facets of RNA-binding protein HuR

“…The HuR/COX-2 axis participates in cell migration and vascular damage. This study also suggests that HuR might be a novel target to modulate vascular remodeling in cardiovascular diseases [16]. Ischemia induced cardiomyocytes loss plays a prominent role in the pathophysiology of cardiac remodeling after MI.…”

Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells

“…We demonstrate that NOX-1-derived O 2 •− presumably under the influence of HuR, participates in cell migration since the potentiation induced by AngII+IL-1β on VSMC migration was inhibited by pharmacological inhibition and knockdown of both NOX-1 and HuR. This might have a role in end organ damage in cardiovascular pathologies associated with increased local levels of NOX-1 and/or HuR including AngII-induced hypertension [32,45], carotid ligation mouse model [32] and other vascular injuries like arterialized saphenous vein or atherosclerotic plaques [46]. Moreover, NOX-4 overexpression further increased IL-1β-induced VSMC migration, suggesting that both NOX-1 and NOX-4 participate in cell migration in inflammatory conditions.…”

“…Specifically, ERK1/2 can phosphorylate HuR modifying its activity in a lung cancer cell line [30] or its location in hepatic stellate [31]. In addition, we have previously shown that AngII+IL-1β increased HuR cytoplasmic localization and this effect was abolished by ERK1/2 inhibition [32]. More importantly, this regulation has a functional role on enzyme activity, since we demonstrate that the synergistically increased NADPH oxidase activity and O 2 •− production induced by AngII plus IL-1β, were abolished by NOX-1 and HuR blockade using pharmacological strategies.…”

Interaction between C2ORF68 and HuR in human colorectal cancer

“…HuR modulates posttranscriptional processing of target premRNAs or mRNA stabilization and translation through interaction with AU-rich elements (ARE) within 3'-untranslated regions (UTRs) of the target mRNAs to transformation (24). Furthermore, it has been shown that HuR stabilizes mRNAs that encode p53 and WEE1 (25), activates ATF2 (26), Jun D (27) and XIAP (28) and enhances the translation of mRNAs that encode c-Myc (29), ICH-1 (30) and IL-1β (31). Many of these transcripts are reported to participate in certain key cellular processes including cell proliferation, cell apoptosis, angiogenesis, immune response and metastasis.…”