scholarly journals [18F]Fluorothymidine Uptake in the Porcine Pancreatic Elastase-Induced Model of Abdominal Aortic Aneurysm

2021 ◽  
Vol 7 (8) ◽  
pp. 130
Author(s):  
Richa Gandhi ◽  
Joanna Koch-Paszkowski ◽  
Charalampos Tsoumpas ◽  
Marc A. Bailey
Keyword(s):  
Murine Model ◽  
Ex Vivo ◽  
Aortic Rupture ◽  
Aortic Aneurysms ◽  
Preclinical Model ◽  
Pancreatic Elastase ◽  
Abdominal Aortic ◽  
Pet Ct ◽  
Porcine Pancreatic Elastase

The porcine pancreatic elastase (PPE) model is a common preclinical model of abdominal aortic aneurysms (AAA). Some notable characteristics of this model include the low aortic rupture rate, non-progressive disease course, and infra-renal AAA formation. Enhanced [18F]fluorothymidine ([18F]FLT) uptake on positron emission tomography/computed tomography (PET/CT) has previously been reported in the angiotensin II-induced murine model of AAA. Here, we report our preliminary findings of investigating [18F]FLT uptake in the PPE murine model of AAA. [18F]FLT uptake was found to be substantially increased in the abdominal areas recovering from the surgery, whilst it was not found to be significantly increased within the PPE-induced AAA, as confirmed using in vivo PET/CT and ex vivo whole-organ gamma counting (PPE, n = 7; controls, n = 3). This finding suggests that the [18F]FLT may not be an appropriate radiotracer for this specific AAA model, and further studies with larger sample sizes are warranted to elucidate the pathobiology contributing to the reduced uptake of [18F]FLT in this model.

scholarly journals Morphological and Biomechanical Differences in the Elastase and AngIIapoE−/−Rodent Models of Abdominal Aortic Aneurysms

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Evan H. Phillips ◽  
Alexa A. Yrineo ◽  
Hilary D. Schroeder ◽  
Katherine E. Wilson ◽  
Ji-Xin Cheng ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Aortic Aneurysms ◽  
Circulating Biomarkers ◽  
Induction Method ◽  
Future Studies ◽  
Disease Characteristics ◽  
Abdominal Aortic ◽  
Extracellular Matrix Molecules ◽  
Biomechanical Parameters

An abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease with multifactorial development and progression. Two preclinical models of the disease (elastase perfusion and angiotensin II infusion in apolipoprotein-E-deficient animals) have been developed to study the disease during its initiation and progression. To date, most studies have usedex vivomethods to examine disease characteristics such as expanded aortic diameter or analytic methods to look at circulating biomarkers. Herein, we provide evidence fromin vivoultrasound studies of the temporal changes occurring in biomechanical parameters and macromolecules of the aortic wall in each model. We present findings from 28-day studies in elastase-perfused rats and AngIIapoE−/−mice. While each model develops AAAs specific to their induction method, they both share characteristics with human aneurysms, such as marked changes in vessel strain and blood flow velocity. Histology and nonlinear microscopy confirmed that both elastin and collagen, both important extracellular matrix molecules, are similarly affected in their levels and spatial distribution. Future studies could make use of the differences between these models in order to investigate mechanisms of disease progression or evaluate potential AAA treatments.

scholarly journals Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms

2021 ◽  
Vol 218 (6) ◽  
Author(s):  
Frank M. Davis ◽  
Lam C. Tsoi ◽  
William J. Melvin ◽  
Aaron denDekker ◽  
Rachael Wasikowski ◽  
...  
Keyword(s):  
Aortic Rupture ◽  
Critical Role ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Pharmacologic Therapy ◽  
Gene Promoters ◽  
Macrophage Phenotype ◽  
Inflammatory Gene ◽  
Abdominal Aortic

Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB–mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II–induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.

scholarly journals Effect of Doxycycline on Survival in Abdominal Aortic Aneurysms in a Mouse Model

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Lisa C. Adams ◽  
Julia Brangsch ◽  
Jan O. Kaufmann ◽  
Dilyana B. Mangarova ◽  
Jana Moeckel ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ex Vivo ◽  
Endothelial Damage ◽  
Aortic Aneurysms ◽  
Clinical Dose ◽  
Doxycycline Treatment ◽  
Abdominal Aortic ◽  
Significant Difference ◽  
Aneurysm Growth

Background. Currently, there is no reliable nonsurgical treatment for abdominal aortic aneurysm (AAA). This study, therefore, investigates if doxycycline reduces AAA growth and the number of rupture-related deaths in a murine ApoE−/− model of AAA and whether gadofosveset trisodium-based MRI differs between animals with and without doxycycline treatment. Methods. Nine ApoE−/− mice were implanted with osmotic minipumps continuously releasing angiotensin II and treated with doxycycline (30 mg/kg/d) in parallel. After four weeks, MRI was performed at 3T with a clinical dose of the albumin-binding probe gadofosveset (0.03 mmol/kg). Results were compared with previously published wild-type control animals and with previously studied ApoE−/− animals without doxycycline treatment. Differences in mortality were also investigated between these groups. Results. In a previous study, we found that approximately 25% of angiotensin II-infused ApoE−/− mice died, whereas in the present study, only one out of 9 angiotensin II-infused and doxycycline-treated ApoE−/− mice (11.1%) died within 4 weeks. Furthermore, doxycycline-treated ApoE−/− mice showed significantly lower contrast-to-noise (CNR) values ( p = 0.017 ) in MRI compared to ApoE−/− mice without doxycycline treatment. In vivo measurements of relative signal enhancement (CNR) correlated significantly with ex vivo measurements of albumin staining (R2 = 0.58). In addition, a strong visual colocalization of albumin-positive areas in the fluorescence albumin staining with gadolinium distribution in LA-ICP-MS was shown. However, no significant difference in aneurysm size was observed after doxycycline treatment. Conclusion. The present experimental in vivo study suggests that doxycycline treatment may reduce rupture-related deaths in AAA by slowing endothelial damage without reversing aneurysm growth.

scholarly journals Animal Model Dependent Response to Pentagalloyl Glucose in Murine Abdominal Aortic Injury

2021 ◽  
Vol 10 (2) ◽  
pp. 219
Author(s):  
Jennifer L. Anderson ◽  
Elizabeth E. Niedert ◽  
Sourav S. Patnaik ◽  
Renxiang Tang ◽  
Riley L. Holloway ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Aortic Injury ◽  
Aortic Aneurysms ◽  
Maximum Diameter ◽  
Ultrasound Images ◽  
Infrarenal Aorta ◽  
High Frequency Ultrasound ◽  
Abdominal Aortic ◽  
Pentagalloyl Glucose

Abdominal aortic aneurysms (AAAs) are a local dilation of the aorta and are associated with significant mortality due to rupture and treatment complications. There is a need for less invasive treatments to prevent aneurysm growth and rupture. In this study, we used two experimental murine models to evaluate the potential of pentagalloyl glucose (PGG), which is a polyphenolic tannin that binds to and crosslinks elastin and collagen, to preserve aortic compliance. Animals underwent surgical aortic injury and received 0.3% PGG or saline treatment on the adventitial surface of the infrarenal aorta. Seventeen mice underwent topical elastase injury, and 14 mice underwent topical calcium chloride injury. We collected high-frequency ultrasound images before surgery and at 3–4 timepoints after. There was no difference in the in vivo effective maximum diameter due to PGG treatment for either model. However, the CaCl2 model had significantly higher Green–Lagrange circumferential cyclic strain in PGG-treated animals (p < 0.05). While ex vivo pressure-inflation testing showed no difference between groups in either model, histology revealed reduced calcium deposits in the PGG treatment group with the CaCl2 model. These findings highlight the continued need for improved understanding of PGG’s effects on the extracellular matrix and suggest that PGG may reduce arterial calcium accumulation.

scholarly journals Allosteric Activation of PP2A Inhibits Experimental Abdominal Aortic Aneurysm

2021 ◽  
Author(s):  
Xianming Zhou ◽  
Chao Zhang ◽  
Fei Xie ◽  
Wei Wei ◽  
Rui Li ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Murine Model ◽  
Molecular Mechanisms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic ◽  
Phosphatase 2A ◽  
Novel Strategy ◽  
Species Production

Although extremely important, the molecular mechanisms that govern aortic aneurysm (AA) formation and progression are still poorly understood. This deficit represents a critical roadblock toward the development of effective pharmaceutical therapies for the treatment of AA. While dysregulation of Protein Phosphatase 2A (PP2A) is thought to play a role in cardiovascular disease, its role in aortic aneurysm is unknown. The objective of this study is to test the hypothesis that PP2A regulates abdominal aortic aneurysm (AAA) progression in a murine model. In an angiotensin II-induced AAA murine model, the PP2A inhibitor, LB-100, markedly accelerated AAA progression as demonstrated by increased abdominal aortic dilation and mortality. AAA progression was associated with elevated inflammation and extracellular matrix fragmentation, concomitant with increases in both metalloproteinase activity and reactive oxygen species production. Conversely, administration of a novel class of small molecule activators of PP2A (SMAPs) resulted in an antithetical effect. SMAPs effectively reduced AAA incidence along with the corresponding pathologies that were increased with LB-100 treatment. Mechanistically, modulation of PP2A activities in vivo functioned in part via alteration of the ERK1/2 and NFkB signaling pathways, known regulators of AAA progression. These studies, for the first time, demonstrate a role of PP2A in AAA etiology and demonstrate that PP2A activation may represent a novel strategy for the treatment of abdominal aortic aneurysms.

Potential benefits of phytochemicals for abdominal aortic aneurysm

2021 ◽  
Vol 28 ◽  
Author(s):  
Azar Hosseini ◽  
Peter E. Penson ◽  
Arrigo FG Cicero ◽  
Jonathan Golledge ◽  
Khalid Al-Rasadi ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Aortic Rupture ◽  
Extended Period ◽  
Grape Seed ◽  
Aortic Aneurysms ◽  
Double Blind ◽  
Abdominal Aortic ◽  
Potential Benefits

Background: Abdominal aortic aneurysms (AAAs) is an important cause of death in older adults due to aortic rupture. There are currently no effective medical therapies for AAA, with surgery being the only acceptable treatment. There is frequently an extended period between AAA diagnosis and treatment by corrective surgery, during which an effective drug therapy could prevent or delay the need for AAA repair. Objective: The aim of this review was to critically summarize prior research investigating the potential benefits of phytochemicals in preventing or treating AAA. Methods: In vitro, in vivo and human studies examining the effect of phytochemicals in AAA models and patients were critically summarised. Results: Some preliminary data support the further investigation of curcumin, radix astragali, grape seed polyphenols, resveratrol, Ginkgo biloba extract (EGb 761), Ginsenoside Rb1, Dan Hong, Epigallocatechin-3-gallate, Baicalein, Fucoidan, Quercetin and Salvianolic acid as potential treatments for AAA. Conclusion: Experimental in vivo and in vitro studies suggest the potential benefits of a number of medicinal herbs and phytochemicals in preventing or reducing the progression of AAA. In order to assess whether these findings can be translated into proven treatments, will require adequately designed double-blind randomized clinical trials.

Investigation of the Observed Rupture Lines in Abdominal Aortic Aneurysms Using Crack Propagation Simulations

2019 ◽  
Vol 141 (7) ◽  
Author(s):  
S. Attarian ◽  
S. Xiao ◽  
T. C. Chung ◽  
E. S. da Silva ◽  
M. L. Raghavan
Keyword(s):  
Crack Propagation ◽  
Ex Vivo ◽  
Wall Stress ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic ◽  
Subject Specific ◽  
Study Population ◽  
Peak Wall Stress

The objective of the study is to use crack propagation simulation to study the rupture site characteristics in ruptured abdominal aortic aneurysms (AAA). In a study population of four ruptured AAA harvested whole from cadavers, the rupture lines were precisely documented. The wall properties such as thickness and material parameters were experimentally determined. Using subject-specific three-dimensional (3D) geometry and a finite elastic isotropic material model with subject-specific parameters, crack propagation simulations were conducted based on basic fracture mechanics principles to investigate if and how localized weak spots may have led to the rupture lines observed upon harvest of ruptured AAA. When an initial crack was imposed at the site of peak wall stress, the propagated path did not match the observed rupture line. This indicates that in this study population, the peak wall stress was unlikely to have caused the observed rupture. When cracks were initiated at random locations in the AAA along random orientations and for random initial lengths, the orientation of the resulting propagated rupture line was always longitudinal. This suggests that the AAA morphology predisposes the AAA to rupture longitudinally, which is consistent with observations. And finally, it was found that, in this study population, rupture may have initiated at short segments of less than 1 cm length that then propagated to the observed rupture lines. This finding provides some guidance for the spatial resolution (approx. 1 cm) of weak spots to investigate for in AAA during ex vivo experimental and in vivo elastography studies. The small study population and lack of a reliable failure model for AAA tissue make these findings preliminary.

scholarly journals Targeting the Extracellular Matrix in Abdominal Aortic Aneurysms Using Molecular Imaging Insights

2021 ◽  
Vol 22 (5) ◽  
pp. 2685
Author(s):  
Lisa Adams ◽  
Julia Brangsch ◽  
Bernd Hamm ◽  
Marcus R. Makowski ◽  
Sarah Keller
Keyword(s):  
Extracellular Matrix ◽  
Molecular Imaging ◽  
Molecular Targets ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Type I ◽  
Target Tissue ◽  
Pharmacologic Treatment ◽  
Abdominal Aortic

This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application.

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