scholarly journals Parallel Murine and Human Aortic Wall Genomics Reveals Metabolic Reprogramming as Key Driver of Abdominal Aortic Aneurysm Progression

2021 ◽  
Author(s):  
Gabor Gäbel ◽  
Bernd H. Northoff ◽  
Amanda Balboa ◽  
Mediha Becirovic‐ Agic ◽  
Marcelo Petri ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Clinical Success ◽  
Metabolic Reprogramming ◽  
Histological Evaluation ◽  
Aortic Dilatation ◽  
Pancreatic Elastase ◽  
Abdominal Aortic ◽  
Porcine Pancreatic Elastase ◽  
The Impact

Background While numerous interventions effectively interfered with abdominal aortic aneurysm (AAA) formation/progression in preclinical models, none of the successes translated into clinical success. Hence, a systematic exploration of parallel and divergent processes in clinical AAA disease and its 2 primary models (the porcine pancreatic elastase and angiotensin‐II infusion [AngII] murine model) was performed to identify mechanisms relevant for aneurysm disease. Methods and Results This study combines Movat staining and pathway analysis for histological and genomic comparisons between clinical disease and its models. The impact of a notable genomic signal for metabolic reprogramming was tested in a rescue trial (AngII model) evaluating the impact of 1‐(4‐pyridinyl)‐3‐(2‐quinolinyl)‐2‐propen‐1‐one (PFK15)‐mediated interference with main glycolytic switch PFKFB3. Histological evaluation characterized the AngII model as a dissection model that is accompanied by adventitial fibrosis. The porcine pancreatic elastase model showed a transient inflammatory response and aortic dilatation, followed by stabilization and fibrosis. Normalization of the genomic responses at day 14 confirmed the self‐limiting nature of the porcine pancreatic elastase model. Clear parallel genomic responses with activated adaptive immune responses, and particularly strong signals for metabolic switching were observed in human AAA and the AngII model. Rescue intervention with the glycolysis inhibitor PFK15 in the AngII model showed that interference with the glycolytic switching quenches aneurysm formation. Conclusions Despite clear morphological contrasts, remarkable genomic parallels exist for clinical AAA disease and the AngII model. The metabolic response appears causatively involved in AAA progression and provides a novel therapeutic target. The clear transient genomic response classifies the porcine pancreatic elastase model as a disease initiation model.

Stereoscopically Observed Deformations of a Compliant Abdominal Aortic Aneurysm Model

2011 ◽  
Vol 133 (11) ◽  
Author(s):  
Clark A. Meyer ◽  
Eric Bertrand ◽  
Olivier Boiron ◽  
Valérie Deplano
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Computational Models ◽  
Imaging System ◽  
Strain Differences ◽  
Cyclic Strain ◽  
Experimental Models ◽  
Body Motion ◽  
Abdominal Aortic ◽  
The Impact

A new experimental setup has been implemented to precisely measure the deformations of an entire model abdominal aortic aneurysm (AAA). This setup addresses a gap between the computational and experimental models of AAA that have aimed at improving the limited understanding of aneurysm development and rupture. The experimental validation of the deformations from computational approaches has been limited by a lack of consideration of the large and varied deformations that AAAs undergo in response to physiologic flow and pressure. To address the issue of experimentally validating these calculated deformations, a stereoscopic imaging system utilizing two cameras was constructed to measure model aneurysm displacement in response to pressurization. The three model shapes, consisting of a healthy aorta, an AAA with bifurcation, and an AAA without bifurcation, were also evaluated with computational solid mechanical modeling using finite elements to assess the impact of differences between material properties and for comparison against the experimental inflations. The device demonstrated adequate accuracy (surface points were located to within 0.07 mm) for capturing local variation while allowing the full length of the aneurysm sac to be observed at once. The experimental model AAA demonstrated realistic aneurysm behavior by having cyclic strains consistent with reported clinical observations between pressures 80 and 120 mm Hg. These strains are 1–2%, and the local spatial variations in experimental strain were less than predicted by the computational models. The three different models demonstrated that the asymmetric bifurcation creates displacement differences but not cyclic strain differences within the aneurysm sac. The technique and device captured regional variations of strain that are unobservable with diameter measures alone. It also allowed the calculation of local strain and removed rigid body motion effects on the strain calculation. The results of the computations show that an asymmetric aortic bifurcation created displacement differences but not cyclic strain differences within the aneurysm sac.

Localized Administration of Doxycycline Suppresses Aortic Dilatation in an Experimental Mouse Model of Abdominal Aortic Aneurysm

2006 ◽  
Vol 20 (2) ◽  
pp. 228-236 ◽  
Author(s):  
Michel A. Bartoli ◽  
Federico E. Parodi ◽  
Jack Chu ◽  
Monica B. Pagano ◽  
Dongli Mao ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Mouse Model ◽  
Aortic Dilatation ◽  
Abdominal Aortic ◽  
Experimental Mouse Model ◽  
Experimental Mouse

Lipid Levels In Patients With Abdominal Aortic Dilatation And Abdominal Aortic Aneurysm (Aaa)

2019 ◽  
Vol 287 ◽  
pp. e160-e161
Author(s):  
M. Kabardieva ◽  
A. Komlev ◽  
I. Kuchin ◽  
A. Kolegaev ◽  
P. Lepilin ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Dilatation ◽  
Lipid Levels ◽  
Abdominal Aortic

The Impact of an Abdominal Aortic Aneurysm on Aortic Wave Reflection

2007 ◽  
Author(s):  
Abigail Swillens ◽  
Lieve Lanoye ◽  
Julie De Backer ◽  
Nikos Stergiopulos ◽  
Frank Vermassen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Wave Reflection ◽  
Numerical Models ◽  
Aortic Aneurysms ◽  
Western World ◽  
Parameter Study ◽  
Linear Wave ◽  
Abdominal Aortic ◽  
The Impact

The economical growth and increased welfare in the Western world have a reverse side, with an increased death toll due to cardiovascular diseases. Among these, aortic aneurysms (a local dilation) are particularly lethal as they may grow unnoticed until rupture occurs. In this study, we assessed the impact of the presence of an abdominal aortic aneurysm on arterial hemodynamics and wave reflection in particular. Experimental and numerical methods were applied. Linear wave separation was used to quantify the reflections; wave intensity analysis was applied to assess the nature of the reflected waves. In both the experimental and numerical models, negative reflections were found in the upper aorta corresponding to a backward expansion wave caused by the sudden expansion of the aorta. A numerical parameter study demonstrated that larger diameters and more compliant aneurysms generate stronger negative reflections.

scholarly journals Deficiency of peroxiredoxin 2 exacerbates angiotensin II-induced abdominal aortic aneurysm

2020 ◽  
Vol 52 (9) ◽  
pp. 1587-1601
Author(s):  
Se-Jin Jeong ◽  
Min Ji Cho ◽  
Na Young Ko ◽  
Sinai Kim ◽  
In-Hyuk Jung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Negative Regulator ◽  
Aortic Dilatation ◽  
Ang Ii ◽  
Peroxiredoxin 2 ◽  
Structural Deterioration ◽  
Abdominal Aortic

Abstract Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease characterized by structural deterioration of the aorta caused by inflammation and oxidative stress, leading to aortic dilatation and rupture. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, has been reported as a potential negative regulator of inflammatory vascular diseases, and it has been identified as a protein that is increased in patients with ruptured AAA compared to patients with nonruptured AAA. In this study, we demonstrated that PRDX2 was a pivotal factor involved in the inhibition of AAA progression. PRDX2 levels were increased in AAA compared with those in normal aortas in both humans and mice. Ultrasound imaging revealed that the loss of PRDX2 accelerated the development of AAA in the early stages and increased AAA incidence in mice infused with angiotensin II (Ang II). Prdx2−/− mice infused with Ang II exhibited increased aortic dilatation and maximal aortic diameter without a change in blood pressure. Structural deterioration of the aortas from Prdx2−/− mice infused with Ang II was associated with increases in the degradation of elastin, oxidative stress, and intramural thrombi caused by microhemorrhages, immature neovessels, and the activation of matrix metalloproteinases compared to that observed in controls. Moreover, an increase in inflammatory responses, including the production of cell adhesion molecules and the accumulation of inflammatory cells and proinflammatory cytokines due to PRDX2 deficiency, accelerated Ang II-induced AAA progression. Our data confirm that PRDX2 plays a role as a negative regulator of the pathological process of AAA and suggest that increasing PRDX2 activity may be a novel strategy for the prevention and treatment of AAA.

scholarly journals Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm

2011 ◽  
Vol 43 (17) ◽  
pp. 993-1003 ◽  
Author(s):  
Joshua M. Spin ◽  
Mark Hsu ◽  
Junya Azuma ◽  
Maureen M. Tedesco ◽  
Alicia Deng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Network Analysis ◽  
Aortic Aneurysm ◽  
Mapk Signaling ◽  
Aortic Dilatation ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Aneurysm Development

We sought to characterize temporal gene expression changes in the murine angiotensin II (ANG II)-ApoE−/− model of abdominal aortic aneurysm (AAA). Aortic ultrasound measurements were obtained over the 28-day time-course. Harvested suprarenal aortic segments were evaluated with whole genome expression profiling at 7, 14, and 28 days using the Agilent Whole Mouse Genome microarray platform and Statistical Analysis of Microarrays at a false discovery rate of <1%. A group of angiotensin-treated mice experienced contained rupture (CR) within 7 days and were analyzed separately. Progressive aortic dilatation occurred throughout the treatment period. However, the numerous early expression differences between ANG II-treated and control were not sustained over time. Ontologic analysis revealed widespread upregulation of inflammatory, immune, and matrix remodeling genes with ANG II treatment, among other pathways such as apoptosis, cell cycling, angiogenesis, and p53 signaling. CR aneurysms displayed significant decreases in TGF-β/BMP-pathway signaling, MAPK signaling, and ErbB signaling genes vs. non-CR/ANG II-treated samples. We also performed literature-based network analysis, extracting numerous highly interconnected genes associated with aneurysm development such as Spp1, Myd88, Adam17 and Lox. 1) ANG II treatment induces extensive early differential expression changes involving abundant signaling pathways in the suprarenal abdominal aorta, particularly wide-ranging increases in inflammatory genes with aneurysm development. 2) These gene expression changes appear to dissipate with time despite continued growth, suggesting that early changes in gene expression influence disease progression in this AAA model, and that the aortic tissue adapts to prolonged ANG II infusion. 3) Network analysis identified nexus genes that may constitute aneurysm biomarkers or therapeutic targets.

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