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.

Surface Parameterization of an Abdominal Aortic Aneurysm to Characterize Geometrical Evolution During Longitudinal Study of Patients

2012 ◽  
Author(s):  
A. Dupay ◽  
P. Snyder ◽  
W. Lee ◽  
S. Baek
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Longitudinal Study ◽  
Aortic Aneurysm ◽  
Disease Progression ◽  
3D Models ◽  
Aortic Aneurysms ◽  
Surrounding Tissue ◽  
Geometrical Parameters ◽  
Abdominal Aortic

For an abdominal aortic aneurysm (AAA) in vivo there are multiple tissues contacting its boundary, none of which have been fully considered for their effect throughout disease progression. Trends such as arterial asymmetry, surface curvature flattening, and arterial tortuosity could be significantly influenced by both surrounding tissue and hemodynamic factors. In order to quantify either the combined or separate influence of such factors during disease progression a precise characterization of aneurysm geometry evolution is needed. Multiple methods for geometrical parameterization of abdominal aortic aneurysms (AAAs) have been previously developed using isolated patient CT scan data but the focus has been mainly on the association of such geometrical parameters with the rupture risk and the efficacy of the parameterization is not fully investigated for a longitudinal study yet (multiple CT scans per patient at progressive intervals) [1]. For this study we have produced a series of 3D models for AAAs in longitudinal studies, developed an arterial centerline generation algorithm, and automated a geometric parameterization procedure for the arterial surfaces. It should be noted that the caliber of our collection of data is relatively rare as it is high resolution, features many patients, and on average has 4–5 images per patient.

The Development of Physiological Compliant Abdominal Aortic Aneurysm Models for In Vitro Flow Studies

2009 ◽  
Author(s):  
Timothy J. Corbett ◽  
Barry J. Doyle ◽  
Anthony Callanan ◽  
Tim M. McGloughlin
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Material Properties ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Flow Loop ◽  
The Past ◽  
Abdominal Aortic

A vast amount of experimental research has been undertaken in the past decade to investigate different aspects of preoperative and postoperative abdominal aortic aneurysms (AAAs). Much of this research has been based on the use of mock arteries in an in vitro flow loop to mimic the behaviour of the abdominal aorta in vivo [1]. These models should be reproducible, have consistent material properties, consistent thickness and be physiological in behaviour.

scholarly journals A Novel Murine Model of Early Abdominal Aortic Aneurysm Reflects Immunopathology in Human Abdominal Aortic Aneurysms

2020 ◽  
Vol 72 (1) ◽  
pp. e189-e190
Author(s):  
Katherin E. Lecki ◽  
Tristan Hayes ◽  
Justin R. King ◽  
Keisin Wang ◽  
Ashley Gutwein ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Murine Model ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic

scholarly journals Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm

2021 ◽  
Vol 118 (31) ◽  
pp. e2107898118
Author(s):  
Chongyang Zhang ◽  
Hongmei Zhao ◽  
Yujun Cai ◽  
Jian Xiong ◽  
Amy Mohan ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Cyclic Nucleotide ◽  
Aortic Aneurysms ◽  
Cyclic Nucleotide Phosphodiesterase ◽  
Causative Role ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is characterized by aorta dilation due to wall degeneration, which mostly occurs in elderly males. Vascular aging is implicated in degenerative vascular pathologies, including AAA. Cyclic nucleotide phosphodiesterases, by hydrolyzing cyclic nucleotides, play critical roles in regulating vascular structure remodeling and function. Cyclic nucleotide phosphodiesterase 1C (PDE1C) expression is induced in dedifferentiated and aging vascular smooth muscle cells (SMCs), while little is known about the role of PDE1C in aneurysm. We observed that PDE1C was not expressed in normal aorta but highly induced in SMC-like cells in human and murine AAA. In mouse AAA models induced by Angiotensin II or periaortic elastase, PDE1C deficiency significantly decreased AAA incidence, aortic dilation, and elastin degradation, which supported a causative role of PDE1C in AAA development in vivo. Pharmacological inhibition of PDE1C also significantly suppressed preestablished AAA. We showed that PDE1C depletion antagonized SMC senescence in vitro and/or in vivo, as assessed by multiple senescence biomarkers, including senescence-associated β-galactosidase activity, γ-H2AX foci number, and p21 protein level. Interestingly, the role of PDE1C in SMC senescence in vitro and in vivo was dependent on Sirtuin 1 (SIRT1). Mechanistic studies further showed that cAMP derived from PDE1C inhibition stimulated SIRT1 activation, likely through a direct interaction between cAMP and SIRT1, which leads to subsequent up-regulation of SIRT1 expression. Our findings provide evidence that PDE1C elevation links SMC senescence to AAA development in both experimental animal models and human AAA, suggesting therapeutical significance of PDE1C as a potential target against aortic aneurysms.

Current evidence and prospects for medical treatment of abdominal aortic aneurysms

VASA ◽  
2005 ◽  
Vol 34 (4) ◽  
pp. 217-223 ◽  
Author(s):  
Diehm ◽  
Schmidli ◽  
Dai-Do ◽  
Baumgartner
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Medical Treatment ◽  
Endovascular Treatment ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Current Evidence ◽  
Significant Morbidity ◽  
Abdominal Aortic ◽  
Risk Of Rupture

Abdominal aortic aneurysm (AAA) is a potentially fatal condition with risk of rupture increasing as maximum AAA diameter increases. It is agreed upon that open surgical or endovascular treatment is indicated if maximum AAA diameter exceeds 5 to 5.5cm. Continuing aneurysmal degeneration of aortoiliac arteries accounts for significant morbidity, especially in patients undergoing endovascular AAA repair. Purpose of this review is to give an overview of the current evidence of medical treatment of AAA and describe prospects of potential pharmacological approaches towards prevention of aneurysmal degeneration of small AAAs and to highlight possible adjunctive medical treatment approaches after open surgical or endovascular AAA therapy.

Gender differences in abdominal aortic aneurysm therapy – a systematic review

VASA ◽  
2018 ◽  
Vol 47 (4) ◽  
pp. 267-272 ◽  
Author(s):  
Konstanze Stoberock ◽  
Tilo Kölbel ◽  
Gülsen Atlihan ◽  
Eike Sebastian Debus ◽  
Nikolaos Tsilimparis ◽  
...  
Keyword(s):  
Gender Differences ◽  
Abdominal Aortic Aneurysm ◽  
Survival Rate ◽  
Aortic Aneurysm ◽  
Endovascular Treatment ◽  
Aortic Aneurysms ◽  
Lower Survival Rate ◽  
Lower Survival ◽  
Abdominal Aortic ◽  
Risk Of Rupture

Abstract. This article analyses if and to what extent gender differences exist in abdominal aortic aneurysm (AAA) therapy. For this purpose Medline (PubMed) was searched from January 1999 to January 2018. Keywords were: “abdominal aortic aneurysm”, “gender”, “prevalence”, “EVAR”, and “open surgery of abdominal aortic aneurysm”. Regardless of open or endovascular treatment of abdominal aortic aneurysms, women have a higher rate of complications and longer hospitalizations compared to men. The majority of studies showed that women have a lower survival rate for surgical and endovascular treatment of abdominal aneurysms after both elective and emergency interventions. Women receive less surgical/interventional and protective medical treatment. Women seem to have a higher risk of rupture, a lower survival rate in AAA, and a higher rate of complications, regardless of endovascular or open treatment. The gender differences may be due to a higher age of women at diagnosis and therapy associated with higher comorbidity, but also because of genetic, hormonal, anatomical, biological, and socio-cultural differences. Strategies for treatment in female patients must be further defined to optimize outcome.

scholarly journals A 60-year-old woman with asymptomatic total thoracic–abdominal aortic aneurysm

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jianying Deng ◽  
Wei Liu
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Effective Treatment ◽  
Clinical Symptoms ◽  
Aortic Aneurysms ◽  
Case Presentation ◽  
Second Stage ◽  
Aortic Replacement ◽  
Abdominal Aortic ◽  
Thoracoabdominal Aortic Replacement

Abstract Introduction Total thoracic–abdominal aortic aneurysm is a rare disease in cardiovascular surgery, with high surgical risk and high mortality. Surgery is considered the most effective treatment for total aortic aneurysms. Case presentation Our group admitted a 60-year-old female patients with asymptomatic complex total thoracic–abdominal aortic aneurysm, and successfully performed two-staged surgery, namely Bentall + Sun’s operation in the first-stage and thoracoabdominal aortic replacement in the second-stage. The results of the surgery were satisfactory. Conclusions Patients with total thoracic–abdominal aortic aneurysm may not have typical clinical symptoms and require a careful and comprehensive physical examination and related auxiliary examinations by clinicians. Staged repair of total thoracic–abdominal aortic aneurysms is still a safe and effective treatment.

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

Circulation ◽  
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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