Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice

AbstractAbdominal aortic aneurysm (AAA) formation and expansion is highly complex and multifactorial, and the improvement of animal models is an important step to enhance our understanding of AAA pathophysiology. In this study, we explore our ability to influence aneurysm growth in a topical elastase plus β-Aminopropionitrile (BAPN) mouse model by varying elastase concentration and by altering the cross-linking capability of the tissue. To do so, we assess both chronic and acute effects of elastase concentration using volumetric ultrasound. Our results suggest that the applied elastase concentration affects initial elastin degradation, as well as long-term vessel expansion. Additionally, we assessed the effects of BAPN by (1) removing it to restore the cross-linking capability of tissue after aneurysm formation and (2) adding it to animals with stable aneurysms to interrupt cross-linking. These results demonstrate that, even after aneurysm formation, lysyl oxidase inhibition remains necessary for continued expansion. Removing BAPN reduces the aneurysm growth rate to near zero, resulting in a stable aneurysm. In contrast, adding BAPN causes a stable aneurysm to expand. Altogether, these results demonstrate the ability of elastase concentration and BAPN to modulate aneurysm growth rate and severity. The findings open several new areas of investigation in a murine model that mimics many aspects of human AAA.

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Inhalational Carbon Monoxide Protects from Abdominal Aortic Aneurysm Formation in Mice

Journal of Surgical Research ◽

10.1016/j.jss.2011.11.254 ◽

2012 ◽

Vol 172 (2) ◽

pp. 201

Author(s):

R.M. McEnaney ◽

C. Go ◽

B. Liu ◽

E. Tzeng

Keyword(s):

Carbon Monoxide ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Aneurysm Formation ◽

Abdominal Aortic

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Rapamycin Treatment Attenuates Angiotensin II -induced Abdominal Aortic Aneurysm Formation via VSMC Phenotypic Modulation and Down-regulation of ERK1/2 Activity

Current Medical Science ◽

10.1007/s11596-018-1851-z ◽

2018 ◽

Vol 38 (1) ◽

pp. 93-100 ◽

Cited By ~ 6

Author(s):

Fei-fei Li ◽

Xiao-ke Shang ◽

Xin-ling Du ◽

Shu Chen

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Phenotypic Modulation ◽

Down Regulation ◽

Rapamycin Treatment ◽

Aneurysm Formation ◽

Abdominal Aortic

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Hexarelin attenuates abdominal aortic aneurysm formation by inhibiting SMC phenotype switch and inflammasome activation

Microvascular Research ◽

10.1016/j.mvr.2021.104280 ◽

2021 ◽

pp. 104280

Author(s):

Bo Jiang ◽

Mo Wang ◽

Xue Li ◽

Pengwei Ren ◽

Guangxin Li ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Inflammasome Activation ◽

Aneurysm Formation ◽

Abdominal Aortic ◽

Phenotype Switch

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Abstract 286: Loss of Smad3 Exacerbates Abdominal Aortic Aneurysm Formation With Enhanced Inflammation in an Experimental Mouse Model

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a286 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Xiaohua Dai ◽

Anandita Arora ◽

Jianbin Shen ◽

Hong Jiang ◽

Li Li

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Calcium Chloride ◽

The United States ◽

Protective Role ◽

Elastic Fibers ◽

Aneurysm Formation ◽

Abdominal Aortic ◽

The Media ◽

Chloride Treatment

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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