Abstract 122: STAT3 Mediates Toll-Like Receptor 4--Dependent Abdominal Aortic Aneurysm Formation in Angiotensin II--Treated ApoE-/- Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Zhexue Qin ◽  
Ho-Jin Park ◽  
Debbie Beasley ◽  
Jonas Galper ◽  
Yali Zhang
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Diameter ◽  
Tlr4 Expression ◽  
Toll Like Receptor 4 ◽  
Abdominal Aortic ◽  
Life Threatening ◽  
Increased Activity ◽  
Stimulation Of

Abdominal aortic aneurysm (AAAs) is a life threatening disease and currently the only treatment is surgical or endovascular repair. Using an animal model for AngiotensinII (AngII) mediated AAA formation in the ApoE-/- mouse, we demonstrate that AAA formation is dependent on the activation of the JAK/STAT pathway. STAT3 activity was increased in the abdominal aortas of Ang II treated ApoE-/- mice. Treatment of ApoE-/- mice with AngII and the p-STAT3 inhibitor S3I-201 decreased the incidence of AAA formation and aortic diameter by greater than 50% compared to placebo. While AngII treatment increased activity of MMP2 and MMP9 in aortas of ApoE-/- mice, S3I-201 treatment inhibited p-STAT3 stimulation and decreased MMP2 and MMP9 activity to levels similar to those in control aortas. The increase in p-STAT3 levels and the secretion of MMP2 and MMP9 in AngII treated bone marrow derived macrophages (BDMs) from ApoE-/- mice was inhibited by pretreatment with S3I-201. Interestingly, AngII stimulated TLR4 expression in AAAs and in BDMs from ApoE-/- mice. Based on these findings we determined the role of TLR4 on AAA formation and p-STAT3 stimulation in ApoE-/-TLR4-/- mice. The incidence of AAA formation, increase in aortic diameter and MMP2 and MMP9 activity were markedly decreased in AngII treated ApoE-/-TLR4-/- mice compared to ApoE-/- controls. Importantly, AngII stimulation of p-STAT3 was also decreased in ApoE-/-TLR4-/- mice compared to control. Similar effects on AngII stimulated p-STAT3 and activity of MMP2 and MMP9 were demonstrated in BMDs from ApoE-/-TLR4-/- mice. Treatment of ApoE-/- mice with the TLR4 inhibitor Eritoran (Eisai, Inc) also decreased the incidence and severity of AAAs, MMPs secretion and p-STAT3 activity. Finally, we determined that S3I-201 decreased AngII stimulated TLR4 expression in AngII treated ApoE-/- mice and in BDM from ApoE-/- mice compared to placebo. These data supported the conclusion that AngII stimulation of AAAs is mediated via a TLR4 dependent activation of p-STAT3 and that both p-STAT3 and TLR4 might be potential therapeutic targets for the treatment of AAAs.

scholarly journals Nuclear Receptor Nur77 Protects Against Abdominal Aortic Aneurysm by Ameliorating Inflammation Via Suppressing LOX‐1

2021 ◽  
Author(s):  
Hengyuan Zhang ◽  
Na Geng ◽  
Lingyue Sun ◽  
Xinyu Che ◽  
Qingqing Xiao ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Nuclear Receptor ◽  
Genetic Manipulation ◽  
Inflammatory Diseases ◽  
Bioinformatics Analyses ◽  
Beneficial Effects ◽  
Abdominal Aortic ◽  
Life Threatening

Background Abdominal aortic aneurysm (AAA) is a life‐threatening vascular disorder characterized by chronic inflammation of the aortic wall, which lacks effective pharmacotherapeutic remedies and has an extremely high mortality. Nuclear receptor NR4A1 (Nur77) functions in various chronic inflammatory diseases. However, the influence of Nur77 on AAA has remained unclear. Herein, we sought to determine the effects of Nur77 on the development of AAA. Methods and Results We observed that Nur77 expression decreased significantly in human and mice AAA lesions. Deletion of Nur77 accelerated the development of AAA in mice, as evidenced by increased AAA incidence, abdominal aortic diameters, elastin fragmentation, and collagen content. Consistent with genetic manipulation, pharmacological activation of Nur77 by celastrol showed beneficial effects against AAA. Microscopic and molecular analyses indicated that the detrimental effects of Nur77 deficiency were associated with aggravated macrophage infiltration in AAA lesions and increased pro‐inflammatory cytokines secretion and matrix metalloproteinase (MMP‐9) expression. Bioinformatics analyses further revealed that LOX‐1 was upregulated by Nur77 deficiency and consequently increased the expression of cytokines and MMP‐9. Moreover, rescue experiments verified that LOX‐1 notably aggravated inflammatory response, an effect that was blunted by Nur77. Conclusions This study firstly demonstrated a crucial role of Nur77 in the formation of AAA by targeting LOX‐1, which implicated Nur77 might be a potential therapeutic target for AAA.

scholarly journals Lower levels of Caveolin-1 and higher levels of endothelial nitric oxide synthase are observed in abdominal aortic aneurysm patients treated with simvastatin

2018 ◽  
Vol 65 (1) ◽  
pp. 111-118 ◽  
Author(s):  
Karolina Kowalska ◽  
Dominika E Habrowska-Górczyńska ◽  
Christoph Neumayer ◽  
Michael Bolliger ◽  
Christoph Domenig ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Enos Expression ◽  
Toll Like Receptor 4 ◽  
Simvastatin Treatment ◽  
Caveolin 1 ◽  
Abdominal Aortic ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

This study was undertaken to verify if simvastatin modulates Cav-1/eNOS expression and if this modulation is associated with changes in pro- and anti-inflammatory cytokines and Toll-like receptor 4 (TLR4) in abdominal aortic aneurysm (AAA). It was 1:2 case-control study of non-statin (n=12) and simvastatin-treated patients (n=24) who underwent open AAA repair. Simvastatin treatment significantly and dose-dependently decreased Cav-1 and increased eNOS expression in AAA wall (p<0.05 and p<0.01, respectively). The changes in Cav-1 and eNOS were associated with a trend towards decreased concentration of IL-6 and IL-17 (p>0.05) and increased concentration of IL-10 (p=0.055) but not with TLR4 expression suggesting other mechanism of simvastatin influence on Cav-1 and eNOS in AAA wall. Simvastatin may modulate Cav-1 and eNOS expression in aneurysmal wall indicating a new beneficial role of statins in AAA patients.

scholarly journals Prospect of positron emission tomography for abdominal aortic aneurysm risk stratification

2021 ◽  
Author(s):  
Richa Gandhi ◽  
Michael Bell ◽  
Marc Bailey ◽  
Charalampos Tsoumpas
Keyword(s):  
Positron Emission Tomography ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Risk Stratification ◽  
Patient Management ◽  
Emission Tomography ◽  
Clinical Implementation ◽  
Positron Emission ◽  
Abdominal Aortic

AbstractAbdominal aortic aneurysm (AAA) disease is characterized by an asymptomatic, permanent, focal dilatation of the abdominal aorta progressing towards rupture, which confers significant mortality. Patient management and surgical decisions rely on aortic diameter measurements via abdominal ultrasound surveillance. However, AAA rupture can occur at small diameters or may never occur at large diameters, implying that anatomical size is not necessarily a sufficient indicator. Molecular imaging may help identify high-risk patients through AAA evaluation independent of aneurysm size, and there is the question of the potential role of positron emission tomography (PET) and emerging role of novel radiotracers for AAA. Therefore, this review summarizes PET studies conducted in the last 10 years and discusses the usefulness of PET radiotracers for AAA risk stratification. The most frequently reported radiotracer was [18F]fluorodeoxyglucose, indicating inflammatory activity and reflecting the biomechanical properties of AAA. Emerging radiotracers include [18F]-labeled sodium fluoride, a calcification marker, [64Cu]DOTA-ECL1i, an indicator of chemokine receptor type 2 expression, and [18F]fluorothymidine, a marker of cell proliferation. For novel radiotracers, preliminary trials in patients are warranted before their widespread clinical implementation. AAA rupture risk is challenging to evaluate; therefore, clinicians may benefit from PET-based risk assessment to guide patient management and surgical decisions.

scholarly journals Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 460
Author(s):  
Saray Varona ◽  
Lídia Puertas ◽  
María Galán ◽  
Mar Orriols ◽  
Laia Cañes ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cells ◽  
Progressive Increase ◽  
Phosphodiesterase 4 ◽  
Inflammatory Conditions ◽  
Abdominal Aortic ◽  
Threatening Condition ◽  
Life Threatening ◽  
Effective Therapeutic Strategy

Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy for an array of inflammatory conditions; however, no studies have assessed yet PDE4 in AAA. Here, we used angiotensin II (AngII)-infused apolipoprotein E deficient mice to study the involvement of the PDE4 subfamily in aneurysmal disease. PDE4B but not PDE4D was upregulated in inflammatory cells from both experimental and human AAA. The administration of the PDE4 selective inhibitor rolipram (3 mg/kg/day) to AngII-challenged mice (1000 ng/kg bodyweight/min) protected against AAA formation, limiting the progressive increase in the aortic diameter without affecting the blood pressure. The drug strongly attenuated the rise in vascular oxidative stress (superoxide anion) induced by AngII, and decreased the expression of inflammatory markers, as well as the recruitment of macrophages (MAC3+), lymphocytes (CD3+), and neutrophils (ELANE+) into the vessel wall. Rolipram also normalized the vascular MMP2 expression and MMP activity, preserving the elastin integrity and improving the vascular remodelling. These results point to PDE4B as a new therapeutic target for AAA.

scholarly journals The Role of Geometric Parameters in the Prediction of Abdominal Aortic Aneurysm Wall Stress

2010 ◽  
Vol 39 (1) ◽  
pp. 42-48 ◽  
Author(s):  
E. Georgakarakos ◽  
C.V. Ioannou ◽  
Y. Kamarianakis ◽  
Y. Papaharilaou ◽  
T. Kostas ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Wall Stress ◽  
Geometric Parameters ◽  
Aneurysm Wall ◽  
Abdominal Aortic ◽  
Abdominal Aortic Aneurysm Wall

scholarly journals Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm

2011 ◽  
Vol 91 (2) ◽  
pp. 358-367 ◽  
Author(s):  
Hidehiro Kaneko ◽  
Toshihisa Anzai ◽  
Toshiyuki Takahashi ◽  
Takashi Kohno ◽  
Masayuki Shimoda ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Abdominal Aortic Aneurysm ◽  
Growth Factor ◽  
Aortic Aneurysm ◽  
Vascular Endothelial ◽  
Abdominal Aortic ◽  
Endothelial Growth Factor

scholarly journals SM22α Loss Contributes to Apoptosis of Vascular Smooth Muscle Cells via Macrophage-Derived circRasGEF1B

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Pin Lv ◽  
Ya-Juan Yin ◽  
Peng Kong ◽  
Li Cao ◽  
Hao Xi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Inflammatory Cell ◽  
Activated Macrophages ◽  
Abdominal Aortic ◽  
Specific Manner ◽  
Higher Sensitivity

Vascular smooth muscle cell (VSMC) apoptosis is a major defining feature of abdominal aortic aneurysm (AAA) and mainly caused by inflammatory cell infiltration. Smooth muscle (SM) 22α prevents AAA formation through suppressing NF-κB activation. However, the role of SM22α in VSMC apoptosis is controversial. Here, we identified that SM22α loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22α enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by Sm22α-/- VSMCs via upregulating VCAM-1 expression. The ratio of apoptosis was increased by 1.62-fold in VSMCs treated with the conditional media (CM) from activated RAW264.7 cells, compared to that of the control CM ( P < 0.01 ), and apoptosis of Sm22α-/- VSMCs was higher than that of WT VSMCs ( P < 0.001 ). Next, circRasGEF1B from activated macrophages was delivered into VSMCs promoting ZFP36 expression via stabilization of ZFP36 mRNA. Importantly, circRasGEF1B, as a scaffold, guided ZFP36 to preferentially bind to and decay Bcl-2 mRNA in a sequence-specific manner and triggered apoptosis of VSMCs, especially in Sm22α-/- VSMCs. These findings reveal a novel mechanism by which the circRasGEF1B-ZFP36 axis mediates macrophage-induced VSMC apoptosis via decay of Bcl-2 mRNA, whereas Sm22α-/- VSMCs have a higher sensitivity to apoptosis.

scholarly journals Associations of IGF1 and its binding proteins with abdominal aortic aneurysm and aortic diameter in older men

2012 ◽  
Vol 166 (2) ◽  
pp. 191-197 ◽  
Author(s):  
Bu B Yeap ◽  
S A Paul Chubb ◽  
Kieran A McCaul ◽  
Leon Flicker ◽  
Ken K Y Ho ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Binding Proteins ◽  
Older Men ◽  
Community Dwelling ◽  
Aortic Diameter ◽  
Aortic Dilation ◽  
Cross Sectional ◽  
Gh Secretion ◽  
Abdominal Aortic

ObjectiveAbdominal aortic aneurysm (AAA) is most prevalent in older men. GH secretion declines with age resulting in reduced IGF1 levels. IGF1 and its binding proteins (IGFBPs) are expressed in vasculature, and lower IGF1 levels have been associated with cardiovascular risk factors and disease. However, the relationship of the IGF1 system with aortic dilation and AAA is unclear. We tested the hypothesis that circulating IGF1 and IGFBPs are associated with AAA and aortic diameter in older men.DesignA cross-sectional analysis involving 3981 community-dwelling men aged 70–89 years was performed.MethodsAbdominal aortic diameter was measured by ultrasound. Plasma total IGF1, IGFBP1 and IGFBP3 were measured by immunoassays.ResultsAfter adjustment for age, body mass index, waist:hip ratio, smoking, hypertension, dyslipidemia, diabetes, coronary heart disease and serum creatinine, a higher IGF1 level was associated with AAA (odds ratio (OR)/1 s.d. increase 1.18, 95% confidence interval (CI) 1.05–1.33, P=0.006), as was the ratio of IGF1/IGFBP3 (OR=1.22, 95% CI 1.10–1.35, P<0.001). Highest IGF1 concentrations compared with lowest quintile were significantly associated with AAA (quintile (Q) 5 vs Q1: OR=1.80, 95% CI 1.20–2.70, P=0.004) as were IGF1/IGFBP3 ratios (Q5 vs Q1: OR=2.52, 95% CI 1.59–4.02, P<0.001). IGF1 and IGFBP1 were independently associated with aortic diameter (β=0.200, 95% CI 0.043–0.357, P=0.012 and β=0.274, 95% CI 0.098–0.449, P=0.002 respectively).ConclusionsIn older men, higher IGF1 and an increased ratio of IGF1/IGFBP3 are associated with AAA, while IGFBP1 is independently associated with increased aortic diameter. Components of the IGF1 system may contribute to, or be a marker for, aortic dilation in ageing men.

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