scholarly journals Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 154 ◽  
Author(s):  
Gianluca L. Perrucci ◽  
Erica Rurali ◽  
Maria Corlianò ◽  
Maria Balzo ◽  
Michela Piccoli ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Marfan Syndrome ◽  
Thoracic Aortic Aneurysm ◽  
Cyclophilin A ◽  
Aortic Tissue ◽  
Tissue Samples ◽  
Abdominal Aortic ◽  
Tgf Β1 ◽  
In Vitro Treatment

Background: Marfan syndrome (MFS) is a genetic disease, characterized by thoracic aortic aneurysm (TAA), which treatment is to date purely surgical. Understanding of novel molecular targets is mandatory to unveil effective pharmacological approaches. Cyclophilin A (CyPA) and its receptor EMMPRIN are associated with several cardiovascular diseases, including abdominal aortic aneurysm. Here, we envisioned the contribution of CyPA/EMMPRIN axis in MFS-related TAA. Methods: We obtained thoracic aortic samples from healthy controls (HC) and MFS patients’ aortas and then isolated vascular smooth muscle cells (VSMC) from the aortic wall. Results: our findings revealed that MFS aortic tissue samples isolated from the dilated zone of aorta showed higher expression levels of EMMPRIN vs. MFS non-dilated aorta and HC. Interestingly, angiotensin II significantly stimulated CyPA secretion in MFS-derived VSMC (MFS-VSMC). CyPA treatment on MFS-VSMC led to increased levels of EMMPRIN and other MFS-associated pro-fibrotic mediators, such as TGF-β1 and collagen I. These molecules were downregulated by in vitro treatment with CyPA inhibitor MM284. Our results suggest that CyPA/EMMPRIN axis is involved in MFS-related TAA development, since EMMPRIN is upregulated in the dilated zone of MFS patients’ TAA and the inhibition of its ligand, CyPA, downregulated EMMPRIN and MFS-related markers in MFS-VSMC. Conclusions: these insights suggest both a novel detrimental role for CyPA/EMMPRIN axis and its inhibition as a potential therapeutic strategy for MFS-related TAA treatment.

Quantifying the Structural and Mechanical Changes in Elastase Degraded Arteries as an In Vitro Model of Aortic Aneurysm

2011 ◽  
Author(s):  
Ming-Jay Chow ◽  
Jarred Raymund Mondonedo ◽  
Katherine Yanhang Zhang
Keyword(s):  
Aortic Aneurysm ◽  
Structural Changes ◽  
Strain Energy Function ◽  
Wall Stress ◽  
Aneurysm Rupture ◽  
Aortic Tissue ◽  
Clinical Practices ◽  
Abdominal Aortic ◽  
Wall Stiffness

Common characteristics of aortic aneurysm include loss of elastin/smooth muscle cells, increase in fibrillary collagen, and increase in artery diameter [5]. Because of the high mortality rate of aneurysm rupture, it is desirable to be able to predict when a patient should have surgery to repair the dilated tissue. Current clinical practices involve predicting aneurysm rupture based on artery expansion rate and diameter. However, other parameters such as wall stiffness and peak wall stress may offer better predictions as to when an aneurysm will fail [8]. Previous studies have investigated the differences in elastin and collagen content of abdominal aortic tissue with and without abdominal aortic aneurysm (AAA) [1]. In another study, human aortic aneurysm tissue was tested in a biaxial tensile tester and the resulting stress strain curves were fitted using Fung type exponential strain energy function [7]. More extensive modeling of aneurysm tissue has been done by modifying the Holzapfel model to incorporate a parameter that characterizes the tissue weakening before the failure of the inner elastic laminae, ground matrix, or collagen fibers themselves [6]. Previous studies have found compositional and mechanical differences between aneurysm and healthy tissue. In addition, good structurally based models for arteries that are developing aneurysm exist but these are mostly theoretical [6]. In order to improve aneurysm rupture prediction techniques, a better understanding of how structural changes affect the mechanical properties of the artery is necessary.

scholarly journals MiR-574-5p: A Circulating Marker of Thoracic Aortic Aneurysm

2019 ◽  
Vol 20 (16) ◽  
pp. 3924 ◽  
Author(s):  
Boileau ◽  
Cardenas ◽  
Courtois ◽  
Zhang ◽  
Rodosthenous ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Extracellular Vesicles ◽  
Thoracic Aortic Aneurysm ◽  
Characteristic Curve ◽  
Serum Levels ◽  
Aortic Tissue ◽  
Wild Type ◽  
Serum Samples ◽  
Tissue Samples ◽  
Aortic Media

Thoracic aortic aneurysm (TAA) can lead to fatal complications such as aortic dissection. Since aneurysm dimension poorly predicts dissection risk, microRNAs (miRNAs) may be useful to diagnose or risk stratify TAA patients. We aim to identify miRNAs associated with TAA pathogenesis and that are possibly able to improve TAA diagnosis. MiRNA microarray experiments of aortic media tissue samples from 19 TAA patients and 19 controls allowed identifying 232 differentially expressed miRNAs. Using interaction networks between these miRNAs and 690 genes associated with TAA, we identified miR-574-5p as a potential contributor of TAA pathogenesis. Interestingly, miR-574-5p was significantly down-regulated in the TAA tissue compared to the controls, but was up-regulated in serum samples from a separate group of 28 TAA patients compared to 20 controls (p < 0.001). MiR-574-5p serum levels discriminated TAA patients from controls with an area under the receiver operating characteristic curve of 0.87. In the Fbn1C1041G/+ mouse model, miR-574-5p was down-regulated in aortic tissue compared to wild-type (p < 0.05), and up-regulated in plasma extracellular vesicles from Fbn1C1041G/+ mice compared to wild-type mice (p < 0.05). Furthermore, in vascular smooth muscle cells, angiotensin II appears to induce miR-574-5p secretion in extracellular vesicles. In conclusion, miR-574-5p is associated with TAA pathogenesis and may help in diagnosing this disease.

scholarly journals Detection of Pathological Changes in the Aorta during Thoracic Aortic Aneurysm Progression on Molecular Level

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Miroslava Rabajdová ◽  
Peter Urban ◽  
Ivana Špaková ◽  
Artemiou Panagiotis ◽  
Michaela Ferenčáková ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Wall ◽  
Pathological Process ◽  
Aortic Tissue ◽  
Mrna Levels ◽  
Tissue Samples ◽  
Extracellular Matrix Components

The progression of thoracic aortic aneurysm depends on regulation of aortic wall homeostasis and on changes in the structural components of the extracellular matrix, which are affected by multiple molecular signalling pathways. We decided to correlate the diameter of ascending thoracic aneurysm with gene expression of inflammation markers (IL-6, CRP), cytokine receptors (IL-6R, TNFR1, and TNFR2), and extracellular matrix components (Emilin-1, MMP9, and TIMP) for detection of the degree of pathological process of TAA formation. The experimental group was divided into three groups according to the diameter of the aortic aneurysm. Whole blood and tissue samples were properly collected and used for nucleic acid, chromatin, and protein isolation. The mRNA levels were detected by qRT-PCR. For the detection of protein levels a Cytokine Array IV assay kit was used in combination with a biochip analyzer. In aortic tissue, significant positive correlations were found between increased mRNA levels of inflammatory cytokines (CRP and IL-6) on both mRNA levels in tissue and protein from the blood with maximum in stage 3. Changes of gene expression of selected genes can be used for the experimental study of the inflammatory receptor inhibitors during trials targeted on slowing down the progress of aortic wall aneurysm.

scholarly journals Identification of Novel microRNA Profiles Dysregulated in Plasma and Tissue of Abdominal Aortic Aneurysm Patients

2020 ◽  
Vol 21 (13) ◽  
pp. 4600 ◽  
Author(s):  
Emma Plana ◽  
Laura Gálvez ◽  
Pilar Medina ◽  
Silvia Navarro ◽  
Victoria Fornés-Ferrer ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Aortic Tissue ◽  
Tissue Samples ◽  
Entire Study ◽  
Abdominal Aortic ◽  
Study Population ◽  
Interaction Map

microRNAs (miRNAs) are small RNAs that regulate different biological processes. Our objective was to identify miRNAs dysregulated in plasma and tissue of patients with abdominal aortic aneurysm (AAA) and explore new potential targets involved in AAA. Fifty-seven subjects were recruited for a plasma study (30 AAA patients, 16 healthy volunteers and 11 patients with atherosclerosis). The expression level of 179 miRNAs was screened in plasma from a subset of samples, and dysregulated miRNAs were validated in the entire study population. Dysregulated miRNAs were also quantified in aortic tissue of 21 AAA patients and 8 organ donors. Applying a gene set enrichment analysis, an interaction map of dysregulated miRNAs and their targets was built, and selected targets were quantified in tissue samples. miR-27b-3p and miR-221-3p were overexpressed in plasma of AAA patients compared with healthy controls, 1.6 times and 1.9 times, respectively. In AAA tissue, six miRNAs (miR-1, miR-27b-3p, miR-29b-3p, miR-133a-3p, miR-133b, and miR-195-5p) were underexpressed from 1.6 to 4.8 times and four miRNAs (miR-146a-5p, miR-21-5p, miR-144-3p, and miR-103a-3p) were overexpressed from 1.3 to 7.2 times. Thrombospondin-2, a target of miR-195-5p, was increased in AAA tissue and negatively correlated with the expression of miR-195-5p, suggesting their involvement in a common regulatory mechanism.

Abstract 676: Microrna-30 and Cthrc1: Translating Aging into Vascular Stiffness and Abdominal Aortic Aneurysm

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Joshua M Spin ◽  
Wei H Zheng ◽  
Matti Adam ◽  
Uwe Raaz ◽  
Isabel Schellinger ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Calcification ◽  
Vascular Stiffness ◽  
Aortic Tissue ◽  
Down Regulation ◽  
Matrix Deposition ◽  
Age Related ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is a major source of vascular morbidity and mortality, with increasing age representing one of the strongest risk factors. While increases in aortic extra-cellular matrix deposition may be protective, changes in vessel architecture with age result in heterogeneous stiffness and vascular calcification, which appear to pre-dispose to AAA development. MicroRNAs (miRs) are key regulators of vascular homeostasis and pathobiology. Array profiling and qRT-PCR of aneurysmal aortic tissue in a murine AAA model (elastase-infused C57/B6) showed significant down-regulation of the miR-30 family, which is believed to have a role in vascular calcification. Increased age augmented this response, particularly for miR-30a, 30b and 30c. RNASeq profiling of a related AAA model (Ang-II in ApoE-/- KO) showed similar aortic down-regulation. Further, of differentially down-regulated miRs, miR-30 had the highest inverse correlation with mRNA gene targets. One predicted target - Cthrc1 (collagen triple helix repeat containing-1) - was the most consistently and significantly up-regulated gene across all time points in the AAA models. The protein resides within vascular smooth muscle cells (SMCs) and fibroblasts, responds to injury, and may regulate collagen expression and deposition. Immunofluorescence staining of AAA vs. normal aortas revealed increased expression of CTHRC1. We further found that miR-30 family members bind to the CTHRC1 3’ UTR and regulate gene expression in vitro, and that antagomir suppression of miR-30 upregulates CTHRC1 in SMCs. We also demonstrated that signaling pathways known to increase in activity with aging within the aorta, and which are associated with vascular calcification and fibrosis (e.g. IL6-based inflammatory signaling, TGF-β signaling, and BMP-2 signaling) down-regulate miR-30 family expression in SMCs, and inversely up-regulate CTHRC1 expression. Forced overexpression of miR-30 in SMC in vitro down-regulates RUNX2, a key promoter of vascular stiffness and calcification. Taken together, these results suggest a significant role for miR-30 in pathways related to matrix deposition and calcification, regulating aortic pathobiology and age-related susceptibility to AAA.

scholarly journals Osteopontin N-Terminal Function in an Abdominal Aortic Aneurysm From Apolipoprotein E-Deficient Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Hongyang Liu ◽  
Ying Zhang ◽  
Wei Song ◽  
Yancui Sun ◽  
Yinong Jiang
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Factors ◽  
Aortic Tissue ◽  
Binding Motif ◽  
Ang Ii ◽  
Histological Changes ◽  
N Protein ◽  
Abdominal Aortic

The cleavage of osteopontin (OPN) by thrombin results in an N-terminal fragment (OPN-N), which exposes a cryptic integrin-binding motif that promotes the adherence of cells, and plays a proinflammatory role. However, the effect of OPN-N on abdominal aortic aneurysm (AAA) remains unknown. The aim of this study was to investigate the expression of OPN-N in aortic tissue samples obtained from patients, who underwent acute aortic dissection (AD), and normal aorta, effect of OPN-N on angiotensin (Ang) II-induced AAA in mice, and relationship between OPN-N and pyroptosis-related inflammatory factors in vitro. Hematoxylin and eosin staining was conducted to detect histological changes. Next, we detected the expression of the OPN-N protein. Additionally, ApoE−/− mice were divided into four groups: control, control + M5Ab (to block the OPN-N function in mice), Ang II, and Ang II + M5Ab. All mice were euthanized after a 28-day infusion and whole aortas, including thoracic and abdominal aortas, were collected for morphological and histological analysis of the AAA. The OPN-N protein expression was higher in patients with AD than in normal individuals, while histological changes in the aortas of Ang II mice were suppressed in Ang II + M5Ab mice. The expression of OPN-N, NOD-, LRR-, and pyrin domain-containing protein 3, pro-Caspase-1, ASC, Gasdermin-d, interleukin (IL)-18, IL-1β, matrix metalloproteinase (MMP) 2, and MMP9 was lower in the Ang II + M5Ab group than in the Ang II group. The gene expression of monocyte chemoattractant protein-1, IL-6, and tumor necrosis factor-α was suppressed in the aortic tissues of the Ang II + M5Ab group compared with the Ang II group. Moreover, the expression of α-smooth muscle actin was lower in the Ang II group than in the Ang II + M5Ab group. In vitro results showed that the increase in the expression of pyroptosis-related inflammatory factors induced by OPN was mediated through the nuclear factor (NF)-κB pathway. In conclusion, OPN-N promotes AAA by increasing the expression of pyroptosis-related inflammatory factors through the NF-κB pathway, inflammation, and extracellular matrix degradation. These results highlight the potential of OPN-N as a new therapeutic target to prevent AAA expansion.

In vitro effects of apoptosis inhibition of thoracic aortic aneurysm

2007 ◽  
Vol 55 (S 1) ◽  
Author(s):  
SA Mohamed ◽  
M Misfeld ◽  
T Hanke ◽  
W Kuehnel ◽  
HH Sievers
Keyword(s):  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Apoptosis Inhibition ◽  
In Vitro Effects

Abstract 3054: Comparison of Transforming Growth Factor-β1 Expression in Aortic Wall of Thoracic Aortic Aneurysm Versus Dissection

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Shouguo Yang ◽  
Guanggen Cui ◽  
Ramin Beygui ◽  
Fardad Esmailian ◽  
Abbas Ardehali ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Wall ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Underlying Mechanism ◽  
Transforming Growth Factor Β1 ◽  
Fluorescent Intensity ◽  
Nucleus Density ◽  
Tgf Β1

Background The underlying mechanism of thoracic aortic aneurysm (TAA) and dissection(TAD) was undetermined, and one controversy lies in whether they represent the different dvelopement period of the same disorder or totally diferent diseases. This study is in aim to compare the expression and distribution of Transforming Growth Factors(TGF) β1 in the aortic wall of TAA versus TAD patients. Method Aortic specimens were obtained from patients underwent to aortic procedures for TAA (n=38) and TAD (n=20) at UCLA , and control aorta (CN) from organ donnor (n=20). Double immunofluorescent stainning of TGF-β1 and α-smooth muscle actin were performed with paraffin embeded slides for all aortic samples and semiquantified by fluorescent intensity analysis. Histopathologic examination were performed with HE, Verhoeff van-Gieson and Masson’s trichrome stain. Results TAA and TAD patients exhibited an up-regulation of TGF-β1 to 120.3% and 109.6% compared with CN separately (P<0.05), with TAA higher than TAD (P<0.05). TGF-β1 distributed unevenly across aortic wall with the highest levels expression in tunica media, followed by intima then adventitia. In intima, TGF-β1 was expressed at the same level for TAD as CN, but was increased to 115.2% for TAA compared to CN (P<0.05). In media, TGF-β1 increased by 127.2% in TAA and 116.1% in TAD compared to CN (P<0.01), with TAA being higher than TAD (P<0.05). In adventitia, TGF- β1 was up-regulated to 119.6% and 116.7% for TAA and TAD compared to CN (P<0.05). Nucleus density analysis showed cellular plasia in adventitia of TAA and TAD than CN (P<0.05 ), while TAD patients demonstrated a higher nucleus density than TAA in intima and adventitia (P<0.05). α-actin was increased in media of TAA and TAD to 164.5% and 120% than CN (P<0.01 and P<0.05). Attenuated and interrupted elastin and mild to severe cystic medial degeneration were characteristic histopathologic finding in 29 (76.3%) TAA and 17(85%) TAD patients. Conclusions TGF- β1 expression was up-regulated in aortic wall of TAA and TAD compared to CN. The significant higher levels of TGF- β1 in intima and media in TAA versus TAD patients implicated a probable positive effect of TGF- β1 to maintain aortic wall integrity, and/or greater comsamption of TGF- β1 in the aortic dissection.

scholarly journals Carotid surgical cut-down technique for neuroendovascular therapy

2018 ◽  
Vol 25 (3) ◽  
pp. 348-352
Author(s):  
Issei Takano ◽  
Yoshiyuki Matsumoto ◽  
Yoshiko Fujii ◽  
Yuki Inoue ◽  
Yoshiki Sugiura ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Carotid Artery ◽  
Thoracic Aortic Aneurysm ◽  
Case Series ◽  
Aortic Arch Anomaly ◽  
Anticoagulation Agents ◽  
Abdominal Aortic ◽  
Major Vessel ◽  
The Common ◽  
Intracranial Circulation

Background Neuroendovascular therapy is typically performed via the femoral artery, but there are rare cases in which a tortuous upstream angioarchitecture makes it difficult to access the intracranial circulation via this route. Methods In this case series, we describe six cases treated by surgical cut-down in the neck, with puncture of the carotid artery. Antiplatelet and anticoagulation agents were used in all cases. The indications for the technique were postsurgical thoracic aortic aneurysm (two cases), postsurgical abdominal aortic aneurysm (one case), major vessel tortuosity of the common carotid artery (two cases) and aortic arch anomaly (one case). Results The surgical cut-down technique permitted successful neuroendovascular therapy. Although one patient had a small cervical haematoma, he was treated without surgical evacuation. Conclusion Overall, our findings indicate that the surgical cut-down technique is safe and useful for patients in whom the femoral approach is unsuitable.

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