Recent Advances in Molecular Mechanisms of Abdominal Aortic Aneurysm Formation

Introduction Abdominal aortic aneurysm (AAA) is a complex vascular disease that causes more than 10,000 deaths each year in the United States. Extensive studies have been performed in search of pharmaceutical treatment but surgical repair still remains the most effective treatment. TGF-β signaling is an important mechanism in the pathogenesis of aneurysms; however, there is debate as to whether its role is protective or destructive. Smad3 is a major intracellular mediator of the canonical pathway of TGF-β signaling. Hypothesis We hypothesize that Smad3-mediated TGF-β signal pathway plays important roles in the pathogenesis of AAA. Methods To test this hypothesis, we analyze the effects of loss of Smad3 on aneurysm formation in the calcium chloride induced AAA model using Smad3 knockout mice. Results Three weeks after calcium chloride treatment, the abdominal aorta displayed increased dilation, forming aneurysms. Histology and immunohistochemistry analyses show increased cell proliferation and enhanced inflammatory cell infiltration in the media and adventitia of the vessel wall. This was accompanied by elastic fibers degradation, increased MMPs expression and reduced expression of smooth muscle markers. Further analysis showed that the expression and nuclear localization of Smad2 and Smad4 was significantly increased. Conclusions These results demonstrate that Smad3-mediated TGF-β signaling plays a protective role in the pathogenesis of AAA and Smad2/Smad4 upregulation is not sufficient to compensate for the loss of Smad3 in this experimental model.

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Abstract 3718: MMP-12 Inhibitor Reduces Severity of ANGII-induced Aortic Abdominal Aneurysms in apoE−/− Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_473-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Dawn A Savio ◽

Anita R Halpern ◽

Yuchuan Wu ◽

Wei Li ◽

Joseph Sypek ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Vascular Wall ◽

Inflammatory Disorder ◽

Gene Markers ◽

Genetic Ablation ◽

Macrophage Recruitment ◽

Aneurysm Formation ◽

Abdominal Aortic

Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by local connective tissue degradation, macrophage recruitment and infiltration leading to aortic dilation and rupture. Aneurysms of the abdominal aorta represent a significant cardiovascular risk for which inflammation plays an integral role in the defined pathology. Genetic ablation of metalloprotease-12 (MMP-12) eliminates metalloelastase activity and attenuates aneurysm formation in apoE−/− mice. In the current study, a selective MMP-12 inhibitor, WAY-644 was evaluated in the well-established murine model of ANGII-induced aneurysm formation. This inhibitor displays activity for murine MMP-12, IC50 = 6.3 nM by FRET analysis, with low crossreactivity for other MMPs (exception MMP-8), and has established in vivo efficacy in inflammation models. Coadministration of WAY-644 to hyperlipidemic apoE−/− mice during ANGII infusion (1.44 mg/kg) for 28d alters the severity of AngII-induced AAAs as measured by changes in abdominal aortic wet weights and typical AAA classification. As expected, plasma MMP-12 protease activity measured by FRET analysis was inhibited. RNA profiling of abdominal aortic aneurysm tissue characterizes ANGII-induced AAA expansion driven by macrophage infiltration, destructive MMP production and attenuation by MMP-12 inhibition. The transcription of a subset of proinflammatory genes activated with ANGII treatment was repressed by the inhibitor. These genes include quantitative markers of macrophage accumulation in the vessel wall, CD68, MCP1/CCL2, CCR2, MMP-12, and Csf1. Associated reductions in gene markers for inflammation and oxidative stress, ie., heme oxidase (HO), nitric oxide synthase (nos2), Ikbkb, and Stat3 also correlate with MMP-12 antagonism. These changes occur in the absence of lipid changes (TC or TG), or quantitative changes in aortic arch lesions in the ANGII-infused animals. The findings support a mechanism whereby MMP-12 metalloelastase inactivation reduces macrophage recruitment to aneurysmal lesion sites, to lessen activated-macrophage expression of proinflammatory cytokines that figure prominently in vascular wall destruction and the pathogenesis of AAAs.

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Decreased angiotensin converting enzyme expression and experimental abdominal aortic aneurysm formation

Journal of Surgical Research ◽

10.1016/j.jss.2004.07.188 ◽

2004 ◽

Vol 121 (2) ◽

pp. 324

Author(s):

M.J. Eagleton ◽

E. Lynch ◽

K. Hannawa ◽

C. Pearce ◽

D. Woodrum ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Angiotensin Converting Enzyme ◽

Converting Enzyme ◽

Enzyme Expression ◽

Aneurysm Formation ◽

Abdominal Aortic

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Mechanism and Localization of Wall Failure During Abdominal Aortic Aneurysm Formation

Biomedical Simulation - Lecture Notes in Computer Science ◽

10.1007/978-3-540-70521-5_13 ◽

2008 ◽

pp. 119-126 ◽

Cited By ~ 4

Author(s):

Dominik Szczerba ◽

Robert McGregor ◽

Krishnamurthy Muralidhar ◽

Gábor Székely

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Aneurysm Formation ◽

Abdominal Aortic

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Deletion of interleukin-18 attenuates abdominal aortic aneurysm formation

Atherosclerosis ◽

10.1016/j.atherosclerosis.2019.08.003 ◽

2019 ◽

Vol 289 ◽

pp. 14-20 ◽

Cited By ~ 5

Author(s):

Chika Suehiro ◽

Jun Suzuki ◽

Mika Hamaguchi ◽

Kayo Takahashi ◽

Tomoaki Nagao ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Interleukin 18 ◽

Aneurysm Formation ◽

Abdominal Aortic

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IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3602824 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Hao Chai ◽

ZhongHao Tao ◽

YongChao Qi ◽

HaoYu Qi ◽

Wen Chen ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Molecular Mechanisms ◽

Critical Role ◽

Ang Ii ◽

Elastin Degradation ◽

Maximal Diameter ◽

Abdominal Aortic ◽

Primary Mouse

Abdominal aortic aneurysm (AAA) is a vascular disorder that is considered a chronic inflammatory disease. However, the precise molecular mechanisms involved in AAA have not been fully elucidated. Recently, significant progress has been made in understanding the function and mechanism of action of inhibitor of kappa B kinase epsilon (IKKε) in inflammatory and metabolic diseases. The angiotensin II- (Ang II-) induced or pharmacological inhibitors were established to test the effects of IKKε on AAA in vivo. After mice were continuously stimulated with Ang II for 28 days, morphologically, we found that knockout of IKKε reduced AAA formation and drastically reduced maximal diameter and severity. We also observed a decrease in elastin degradation and medial destruction, which were independent of systolic blood pressure or plasma cholesterol concentrations. Western blot analyses and immunohistochemical staining were carried out to measure IKKε expression in AAA tissues and cell lines. AAA phenotype of mice was measured by ultrasound and biochemical indexes. In zymography, immunohistology staining, immunofluorescence staining, and reactive oxygen species (ROS) analysis, TUNEL assay was used to examine the effects of IKKε on AAA progression in AAA mice. IKKε deficiency significantly inhibited inflammatory macrophage infiltration, matrix metalloproteinase (MMP) activity, ROS production, and vascular smooth muscle cell (VSMC) apoptosis. We used primary mouse aortic VSMC isolated from apolipoprotein E (Apoe) −/− and Apoe−/−IKKε−/− mice. Mechanistically, IKKε deficiency blunted the activation of the ERK1/2 pathway. The IKKε inhibitor, amlexanox, has the same impact in AAA. Our results demonstrate a critical role of IKKε in AAA formation induced by Ang II in Apoe−/− mice. Targeting IKKε may constitute a novel therapeutic strategy to prevent AAA progression.

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