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Inhibition of EP4 signaling attenuates aortic aneurysm formation.

ABSTRACT: BACKGROUND: Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E(2) (PGE(2)) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurysm (AAA) formation. We hypothesized that selective blocking of PGE(2), in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA. METHODS AND FINDINGS: Immunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE(2) stimulation increased EP4 protein expression (1.4 ± 0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4 ± 0.03- and 1.7 ± 0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE(-/-) mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01-0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45-87% reduction, P<0.05). Similarly, EP4(+/-)/ApoE(-/-) mice exhibited significantly less AAA formation than EP4(+/+)/ApoE(-/-) mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl(2) application was also reduced in EP4(+/-) mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10-100 nM decreased MMP-2 activation and IL-6 production (0.6 ± 0.06- and 0.7 ± 0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release. CONCLUSION: An EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA.

SUBMITTER: Yokoyama U

PROVIDER: S-EPMC3343028 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Inhibition of EP4 signaling attenuates aortic aneurysm formation.

Yokoyama Utako U Ishiwata Ryo R Jin Mei-Hua MH Kato Yuko Y Suzuki Orie O Jin Huiling H Ichikawa Yasuhiro Y Kumagaya Syun S Katayama Yuzo Y Fujita Takayuki T Okumura Satoshi S Sato Motohiko M Sugimoto Yukihiko Y Aoki Hiroki H Suzuki Shinichi S Masuda Munetaka M Minamisawa Susumu S Ishikawa Yoshihiro Y

PloS one 20120503 5

<h4>Background</h4>Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E(2) (PGE(2)) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurysm (AAA) formation. We hypothesized that selective blocking of PGE(2), in particular, EP4 prostanoid receptor signaling, would attenuate the ...[more]

PMID: 22570740

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Project description: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 AngII type 1a receptor in AAA formation. ?-arrestin (?arr)-2 is a multifunctional scaffolding protein that binds G-protein-coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for ?arr2 in AngII-induced AAA formation is currently unknown. OBJECTIVE:To determine whether ?arr2 played a role in AngII-induced AAA formation in mice. METHODS AND RESULTS:Treatment of ?arr2(+/+) and ?arr2(-/-) mice on the hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that ?arr2 deficiency significantly attenuated AAA formation. ?arr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1?, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE(-/-)/?arr2(+/+) aortas, whereas ?arr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE(-/-)/?arr2(+/+) mice to the level observed in apoE(-/-)/?arr2(-/-) mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE(-/-)/?arr2(+/+) aortas, and ?arr2 deficiency reduced these effects. CONCLUSIONS:?arr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2-mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein-independent, ?arr2-dependent signaling plays a major role in AngII-induced AAA formation.

Project description:Surgical intervention is currently the only option for an abdominal aortic aneurysm (AAA), preventing its rupture and sudden death of a patient. Therefore, it is crucial to determine the pathogenic mechanisms of this disease for the development of effective pharmacological therapies. Oxidative stress is said to be one of the pivotal factors in the pathogenesis of AAAs. Thus, we aimed to evaluate the significance of nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional activity in the development of AAA and to verify if simvastatin, administered as pre- and cotreatment, may counteract this structural malformation. Experiments were performed on mice with inhibited transcriptional activity of Nrf2 (tKO) and wild-type (WT) counterparts. We used a model of angiotensin II- (AngII-) induced AAA, combined with a fat-enriched diet. Mice were administered with AngII or saline for up to 28 days via osmotic minipumps. Simvastatin administration was started 7 days before the osmotic pump placement and then continued until the end of the experiment. We found that Nrf2 inactivation increased the risk of development and rupture of AAA. Importantly, these effects were reversed by simvastatin in tKO mice, but not in WT. The abrupt blood pressure rise induced by AngII was mitigated in simvastatin-treated animals regardless of the genotype. Simvastatin-affected parameters that differed between the healthy structure of the aorta and aneurysmal tissue included immune cell infiltration of the aortic wall, VCAM1 mRNA and protein level, extracellular matrix degradation, TGF-?1 mRNA level, and ERK phosphorylation, but neither oxidative stress nor the level of Angiotensin II Type 1 Receptor (AT1R). Taken together, the inhibition of Nrf2 transcriptional activity facilitates AAA formation in mice, which can be prevented by simvastatin. It suggests that statin treatment of patients with hypercholesterolemia might have not only a beneficial effect in terms of controlling atherosclerosis but also potential AAA prevention.

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Inhibition of EP4 signaling attenuates aortic aneurysm formation.

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Inhibition of EP4 signaling attenuates aortic aneurysm formation.

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