Endothelium as a Potential Target for Treatment of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) was previously ascribed to weaken defective medial arterial/adventitial layers, for example, smooth muscle/fibroblast cells. Therefore, besides surgical repair, medications targeting the medial layer to strengthen the aortic wall are the most feasible treatment strategy for AAA. However, so far, it is unclear whether such drugs have any beneficial effect on AAA prognosis, rate of aneurysm growth, rupture, or survival. Notably, clinical studies have shown that AAA is highly associated with endothelial dysfunction in the aged population. Additionally, animal models of endothelial dysfunction and endothelial nitric oxide synthase (eNOS) uncoupling had a very high rate of AAA formation, indicating there is crucial involvement of the endothelium and a possible pharmacological solution targeting the endothelium in AAA treatment. Endothelial cells have been found to trigger vascular wall remodeling by releasing proteases, or recruiting macrophages along with other neutrophils, into the medial layer. Moreover, inflammation and oxidative stress of the arterial wall were induced by endothelial dysfunction. Interestingly, there is a paradoxical differential correlation between diabetes and aneurysm formation in retinal capillaries and the aorta. Deciphering the significance of such a difference may explain current unsuccessful AAA medications and offer a solution to this treatment challenge. It is now believed that AAA and atherosclerosis are two separate but related diseases, based on their different clinical patterns which have further complicated the puzzle. Therefore, a thorough investigation of the interaction between endothelium and medial/adventitial layer may provide us a better understanding and new perspective on AAA formation, especially after taking into account the importance of endothelium in the development of AAA. Moreover, a novel medication strategy replacing the currently used, but suboptimal treatments for AAA, could be informed with this analysis.

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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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Adipocyte in vascular wall can induce the rupture of abdominal aortic aneurysm

Scientific Reports ◽

10.1038/srep31268 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 22

Author(s):

Hirona Kugo ◽

Nobuhiro Zaima ◽

Hiroki Tanaka ◽

Youhei Mouri ◽

Kenichi Yanagimoto ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Vascular Wall ◽

Abdominal Aortic

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Abstract 486: The Effects of Weekend Admission on the Outcomes and Management of Ruptured Aortic Aneurysms

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.486 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Elliott M Groves ◽

Mahdi Khoshchehreh ◽

Christine Le ◽

Shaista Malik

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Surgical Intervention ◽

Surgical Care ◽

Aortic Aneurysms ◽

High Rate ◽

Ruptured Aortic Aneurysm ◽

Primary Endpoints ◽

Abdominal Aortic ◽

Thoracic And Abdominal

The Effects of Weekend Admission on the Outcomes and Management of Ruptured Aortic Aneurysms Objective: Ruptured aortic aneurysm is a condition with a high rate of mortality that requires prompt surgical intervention. It has been noted that in some conditions requiting such prompt intervention, in-hospital mortality is increased in patients admitted on the weekends as compared to patients admitted on weekdays. We sought to determine if this was indeed the case for both ruptured thoracic and abdominal aortic aneurysm and elucidate the possible reasons. Methods: Using the Nationwide Inpatient Sample (NIS), a publicly available database of inpatient care, we analyzed the incidence of mortality among patients admitted on the weekends compared to weekdays for ruptured aortic aneurysm. Ultimately the care of over 7,000 patients was analyzed for the primary endpoints. We adjusted for demographics, comorbid conditions, hospital characteristics, rates of surgical intervention, timing of surgical intervention and use of additional therapeutic measures. Results: Patients admitted on the weekend for both ruptured thoracic and abdominal aortic aneurysm had a statistically significant increase in mortality as compared to those admitted on the weekdays (OR 2.55 for Thoracic and 1.32 for Abdominal). By our analysis this is likely due to a delay in surgical care on the weekends. Conclusions: Weekend admission for ruptured aortic aneurysm is associated with an increased mortality when compared to those admitted on the weekend and this is likely due to several factors with the most predominant being a delay in surgical intervention.

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Ovariectomy increases the incidence and diameter of abdominal aortic aneurysm in a hypoperfusion-induced abdominal aortic aneurysm animal model

Scientific Reports ◽

10.1038/s41598-019-54829-0 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Chie Miyamoto ◽

Hirona Kugo ◽

Keisuke Hashimoto ◽

Tatsuya Moriyama ◽

Nobuhiro Zaima

Keyword(s):

Growth Rate ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Incidence Rate ◽

Vascular Wall ◽

Vascular Walls ◽

Abdominal Aortic ◽

Male Sex ◽

Aneurysm Diameter ◽

Metalloproteinase 9

AbstractAbdominal aortic aneurysm (AAA) is a vascular disease characterized by weakening of the vascular walls. Male sex is a risk factor for AAA, and peak AAA incidence occurs in men 10 years earlier than in women. However, the growth rate of AAA is faster in women, and women have a higher mortality due to AAA rupture. The mechanisms underlying sex-related differences in AAA remain unknown. Herein, we evaluated the effects of ovariectomy (OVX) on AAA in rats. Upon evaluation of the effects of OVX and AAA induction, AAA incidence rate and the aneurysm diameter increased in the OVX group. However, the histopathology in the developed AAA wall was not different between groups. When the effects of OVX on the vascular wall without AAA induction were evaluated, elastin and collagen levels were significantly decreased. Furthermore, the level of matrix metalloproteinase-9 significantly increased in the OVX group. According to our results, it is speculated that decreased levels of collagen and elastin fibers induced by OVX might be involved in increased incidence rate and diameter of AAA. Weakening of the vascular wall before the onset of AAA might be one reason for the faster rate of AAA growth in women.

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Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm

Clinical Science ◽

10.1042/cs20190399 ◽

2019 ◽

Vol 133 (13) ◽

pp. 1421-1438 ◽

Cited By ~ 7

Author(s):

Miquel Navas-Madroñal ◽

Cristina Rodriguez ◽

Modar Kassan ◽

Joan Fité ◽

José R. Escudero ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Er Stress ◽

Mitochondrial Biogenesis ◽

Atmospheric Pressure Chemical Ionization ◽

Vascular Wall ◽

Protein Levels ◽

Abdominal Aortic ◽

Healthy Donors

Abstract Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a complex aetiology that remains to be fully elucidated. Clinical management of AAA is limited to surgical repair, while an effective pharmacotherapy is still awaited. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been involved in the pathogenesis of cardiovascular diseases (CVDs), although their contribution to AAA development is uncertain. Therefore, we aimed to determine their implication in AAA and investigated the profile of oxysterols in plasma, specifically 7-ketocholesterol (7-KC), as an ER stress inducer. In the present study, we determined aortic ER stress activation in a large cohort of AAA patients compared with healthy donors. Higher gene expression of activating transcription factor (ATF) 6 (ATF6), IRE-1, X-binding protein 1 (XBP-1), C/EBP-homologous protein (CHOP), CRELD2 and suppressor/enhancer of Lin-12-like (SEL1L) and greater protein levels of active ATF6, active XBP1 and of the pro-apoptotic protein CHOP were detected in human aneurysmatic samples. This was accompanied by an exacerbated apoptosis, higher reactive oxygen species (ROS) production and by a reduction in mitochondrial biogenesis in the vascular wall of AAA. The quantification of oxysterols, performed by liquid chromatography-(atmospheric pressure chemical ionization (APCI))-mass spectrometry, showed that levels of 7-KC were significantly higher while those of 7α-hydroxycholesterol (HC), 24-HC and 27-HC were lower in AAA patients compared with healthy donors. Interestingly, the levels of 7-KC correlate with the expression of ER stress markers. Our results evidence an induction of ER stress in the vascular wall of AAA patients associated with an increase in circulating 7-KC levels and a reduction in mitochondrial biogenesis suggesting their implication in the pathophysiology of this disease.

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