β-Arrestin-2 Deficiency Attenuates Abdominal Aortic Aneurysm Formation in Mice.
ABSTRACT Rationale: Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII) and previous studies indicated a primary role for the angiotensin II type 1a (AT1a) receptor, in AAA formation. β-arrestin-2 (βarr2) is a multifunctional scaffolding protein that binds G-protein coupled receptors such as AT1a, and regulates numerous signaling pathways and pathophysiological processes. However, a role for βarr2 in AngII-induced AAA formation is currently unknown. Objective: To determine if βarr2 played a role in AngII-induced AAA formation in mice. Methods and Results: Treatment of βarr2(+/+) and βarr2(-/-) mice on the hyperlipidemic ApoE-/-background or normolipidemic C57BL/6 background with AngII for 28 days indicated that βarr2 deficiency significantly attenuated AAA formation. βarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2 (COX-2), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1α (MIP1α), and macrophage infiltration. AngII also increased the levels of phosphorylated-extracellular signal-regulated kinase 1/2 (p-ERK1/2) in ApoE(-/-)/ βarr2(+/+) aortas, whereas βarr2 deficiency diminished this increase. Furthermore, inhibition of ERK1/2 activation with CI1040 (100mg/kg/day) reduced the level of AngII-induced COX-2 expression in ApoE(-/-)/ βarr2(+/+) mice to the level observed in ApoE(-/-)/ βarr2(-/-) mice. AngII treatment also increased matrix metalloproteinase (MMP) expression and disruption of the elastic layer in ApoE(-/-)/ βarr2(+/+) aortas and βarr2-deficiency reduced these effects. Conclusions:: βarr2 contributes to AngII-induced AAA formation in mice by p-ERK1/2-mediated COX-2 induction and increased inflammation. These studies suggest that for the AT1a receptor, G-protein-independent, βarr2-dependent signaling plays a major role in AngII-induced AAA formation.
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ABSTRACT: To test the hypothesis that angiotensin II (Ang II) could enhance noradrenaline (NA) release from sympathetic nerve endings of the aorta thus contributing to the up-regulation of matrix metalloproteinase 2 (MMP-2) during the formation of aortic dissection (AD). Ang II, NA, MMP-2, MMP-9 of the aorta sample obtained during operation from aortic dissection patients were detected by High Performance Liquid Chromatography and ELISA and compared with controls. Isotope labelling method was used to test the impact of exogenous Ang II and noradrenaline on the NA release and MMP-2, MMP-9 expression on Sprague Dawley (SD) rat aorta rings in vitro. Two kidneys, one clip, models were replicated for further check of that impact in SD rats in vivo. The concentration of Ang II, MMP-2, 9 was increased and NA concentration was decreased in aorta samples from AD patients. Exogenous Ang II enhanced while exogenous NA restrained NA release from aortic sympathetic endings. The Ang II stimulated NA release and the following MMP-2 up-regulation could be weakened by Losartan and chemical sympathectomy. Beta blocker did not influence NA release but down-regulated MMP-2. Long term in vivo experiments confirmed that Ang II could enhance NA release and up-regulate MMP-2. AD is initiated by MMP-2 overexpression as a result of increased NA release from sympathetic nervous endings in response to Ang II. This indicates an interaction of RAS and SAS during the formation of AD.PLoS ONE 10/2013; 8(10):e76922. DOI:10.1371/journal.pone.0076922 · 3.53 Impact Factor
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ABSTRACT: Regulatory mechanisms of the expression of interleukin-10 (IL-10) in brain inflammatory conditions remain elusive. To address this issue, we used multiple primary brain cell cultures to study the expression of IL-10 in lipopolysaccharide (LPS)-elicited inflammatory conditions. In neuron-glia cultures, LPS triggered well-orchestrated expression of various immune factors in the following order: tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and lastly IL-10, and these inflammatory mediators were mainly produced from microglia. While exogenous application of individual earlier-released pro-inflammatory factors (e.g., TNF-α, IL-1β, or PGE2) failed to induce IL-10 expression, removal of LPS from the cultures showed the requirement of continuing presence of LPS for IL-10 expression. Interestingly, genetic disruption of tnf-α, its receptors tnf-r1/r2, and cox-2 and pharmacological inhibition of COX-2 activity enhanced LPS-induced IL-10 production in microglia, which suggests negative regulation of IL-10 induction by the earlier-released TNF-α and PGE2. Further studies showed that negative regulation of IL-10 production by TNF-α is mediated by PGE2. Mechanistic studies indicated that PGE2-elicited suppression of IL-10 induction was eliminated by genetic disruption of the PGE2 receptor EP2 and was mimicked by the specific agonist for the EP2, butaprost, but not agonists for the other three EP receptors. Inhibition of cAMP-dependent signal transduction failed to affect PGE2-mediated inhibition of IL-10 production, suggesting that a G protein-independent pathway was involved. Indeed, deficiency in β-arrestin-1 or β-arrestin-2 abolished PGE2-elicited suppression of IL-10 production. In conclusion, we have demonstrated that COX-2-derived PGE2 inhibits IL-10 expression in brain microglia through a novel EP2- and β-arrestin-dependent signaling pathway.Molecular Neurobiology 09/2014; DOI:10.1007/s12035-014-8889-0 · 5.29 Impact Factor
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ABSTRACT: TGF-β signaling in SMC contributes to the pathogenesis of elastase-induced AAA.•Disruption of TGF-β signaling in SMC can prevent the aneurysm formation.•There is an expression-dependent effect of TGF-β on AAA following elastase application.•Our study suggests the complex and context-dependent roles of TGF-β in aneurysm.Biochemical and Biophysical Research Communications 10/2014; 454(1). DOI:10.1016/j.bbrc.2014.10.053 · 2.28 Impact Factor