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Adiponectin attenuates abdominal aortic aneurysm formation in hyperlipidemic mice.

ABSTRACT: Abdominal aortic aneurysms (AAA) are age-associated, life-threatening inflammatory dilations of the abdominal aorta. Human population studies have shown an association between obesity and AAA formation, but the molecular mechanisms underlying this connection remain largely unexplored. Adiponectin is an anti-inflammatory adipokine that is downregulated in obesity. In this study we evaluated the role of adiponectin in a model of AAA using apolipoprotein E/adiponectin double-knockout (Apoe(-/-)Apn(-/-)) mice.Angiotensin II (Ang II)-infusion in male Apoe(-/-)Apn(-/-) mice led to a higher incidence of AAA and a significant increase of maximal aortic diameter compared with that of Apoe(-/-) mice (2.12 ± 0.07 mm vs. 1.67 ± 0.09 mm, respectively at 28 days). Adiponectin deficiency augmented the early infiltration of macrophages and increased the expression of pro-inflammatory factors in the dilated aortic wall. MMP-2 and MMP-9 activation was also augmented in the aorta of Apoe(-/-)Apn(-/-) mice compared to Apoe(-/-) mice. These data suggest that the downregulation of adiponectin could directly contribute to the elevated incidence of AAA observed in obese individuals.Adiponectin attenuates Ang II-induced vascular inflammation and AAA formation in mice.

SUBMITTER: Yoshida S

PROVIDER: S-EPMC4100794 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Adiponectin attenuates abdominal aortic aneurysm formation in hyperlipidemic mice.

Yoshida Sumiko S Fuster José Javier JJ Walsh Kenneth K

Atherosclerosis 20140523 2

<h4>Objective</h4>Abdominal aortic aneurysms (AAA) are age-associated, life-threatening inflammatory dilations of the abdominal aorta. Human population studies have shown an association between obesity and AAA formation, but the molecular mechanisms underlying this connection remain largely unexplored. Adiponectin is an anti-inflammatory adipokine that is downregulated in obesity. In this study we evaluated the role of adiponectin in a model of AAA using apolipoprotein E/adiponectin double-knock ...[more]

PMID: 24911638

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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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Adiponectin attenuates abdominal aortic aneurysm formation in hyperlipidemic mice.

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Adiponectin attenuates abdominal aortic aneurysm formation in hyperlipidemic mice.

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