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 Epigenetics in Ascending Thoracic Aortic Aneurysm and Dissection

Aorta ◽  
2018 ◽  
Vol 06 (01) ◽  
pp. 001-012 ◽  
Author(s):  
Adeline Boileau ◽  
Mark Lindsay ◽  
Jean-Baptiste Michel ◽  
Yvan Devaux
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Transforming Growth Factor Β ◽  
Cell Protein ◽  
Monogenic Diseases

AbstractThoracic aortic aneurysm (TAA) is an asymptomatic and progressive dilatation of the thoracic aorta. Ascending aortic dissection (AAD) is an acute intraparietal tear, occurring or not on a pre-existing dilatation. AAD is a condition associated with a poor prognosis and a high mortality rate. TAA and AAD share common etiology as monogenic diseases linked to transforming growth factor β signaling pathway, extracellular matrix defect, or smooth muscle cell protein mutations. They feature a complex pathogenesis including loss of smooth muscle cells, altered phenotype, and extracellular matrix degradation in aortic media layer. A better knowledge of the mechanisms responsible for TAA progression and AAD occurrence is needed to improve healthcare, nowadays mainly consisting of aortic open surgery or endovascular replacement. Recent breakthrough discoveries allowed a deeper characterization of the mechanisms of gene regulation. Since alteration in gene expression has been linked to TAA and AAD, it is conceivable that a better knowledge of the causes of this alteration may lead to novel theranostic approaches. In this review article, the authors will focus on epigenetic regulation of gene expression, including the role of histone methylation and acetylation, deoxyribonucleic acid methylation, and noncoding ribonucleic acids in the pathogenesis of TAA and AAD. They will provide a translational perspective, presenting recent data that motivate the evaluation of the potential of epigenetics to diagnose TAA and prevent AAD.

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 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.

Global gene expression profiles reveal an increase in mRNA levels of collagens, MMPs, and TIMPs in late radiation enteritis

2004 ◽  
Vol 287 (4) ◽  
pp. G875-G885 ◽  
Author(s):  
Carine Strup-Perrot ◽  
Denis Mathé ◽  
Christine Linard ◽  
Dominique Violot ◽  
Fabien Milliat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Expression Profiles ◽  
Cdna Array ◽  
Muscularis Propria ◽  
Gelatin Zymography ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Radiation Enteritis ◽  
Mrna Levels ◽  
Fixed Tissue

Radiation enteritis, a common complication of radiation therapy for abdominal and pelvic cancers, is characterized by severe transmural fibrosis associated with mesenchymal cell activation, tissue disorganization, and deposition of fibrillar collagen. To investigate the mechanisms involved in this pathological accumulation of extracellular matrix, we studied gene expression of matrix components along with that of genes involved in matrix remodeling, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). Hybrid selection on high-density cDNA array, real-time RT-PCR, gelatin zymography and imunohistochemistry were used to characterize the mRNA expression profile, activity, and tissue location of extracellular matrix-related genes in radiation enteritis compared with healthy ileum. cDNA array analysis revealed a strong induction of genes coding for collagens I, III, IV, VI, and VIII, SPARC, and tenascin-C, extracellular-matrix degrading enzymes (MMP-1, -2, -3, -14, -18+19), and metalloproteinase inhibitors (TIMP-1, -2, plasminogen activator inhibitor-1) in radiation enteritis. This increase was correlated with the degree of infiltration of the mucosa by inflammatory cells, and the presence of differentiated mesenchymal cells in the submucosa and muscularis propria. Despite the fact that expression of collagens, MMPs, and TIMPs simultaneously increase, quantification of net collagen deposition shows an overall accumulation of collagen. Our results indicate that late radiation enteritis tissues are subjected to active process of fibrogenesis as well as fibrolysis, with a balance toward fibrogenesis. This demonstrates that established fibrotic tissue is not scarred fixed tissue but is subjected to a dynamic remodeling process.

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.

Region-Specific Medial Fiber Micro-Architecture in the Longitudinal-Radial and Circumferential-Radial Planes of Ascending Thoracic Aortic Aneurysm Among Bicuspid and Tricuspid Aortic Valve Patients

2013 ◽  
Author(s):  
Alkiviadis Tsamis ◽  
Julie A. Phillippi ◽  
Ryan G. Koch ◽  
Jeffrey T. Krawiec ◽  
Antonio D’Amore ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Wall ◽  
False Lumen ◽  
True Lumen ◽  
Life Threatening ◽  
The Media ◽  
Intimal Tear

Aortic dissection is a life-threatening cardiovascular emergency with a high potential for death. It usually begins with an intimal tear which permits blood to enter the wall, split the media and create a false lumen, which can reenter the true lumen or exit through the adventitia causing complete rupture. A possible mechanism for dissection of ascending thoracic aortic aneurysm (ATAA) can be the occurrence of blood pressure-induced wall stresses in excess to the adhesive strength between the degenerated aortic wall layers.

P3114Protective effect of SOCS1-based therapy in experimental abdominal aortic aneurysm

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Bernal Uribe ◽  
L Lopez-Sanz ◽  
A Melgar ◽  
S La-Manna ◽  
L Jimenez-Castilla ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Wall ◽  
Janus Kinase ◽  
Toxic Dose ◽  
Altered Expression ◽  
Abdominal Aortic ◽  
Stat Pathway

Abstract Introduction Abdominal aortic aneurysm (AAA) is a multifactorial vascular disease characterized by chronic inflammation, oxidative stress and proteolytic activity in the aortic wall, which contribute to extracellular matrix degradation and aortic dilation. Altered expression and activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have been implicated in several cardiovascular diseases including atherosclerosis and aneurysm formation. Suppressors of cytokine signaling (SOCS) are key negative regulators of JAK/STAT pathway and have been considered an attractive target for therapeutic intervention. AIM We hypothesize that SOCS1 protein could influence AAA development by inhibiting JAK activity and, consequently, STAT activation and target gene expression. Therefore, this study investigates the effect of a SOCS1-derived synthetic peptide in a rodent model of AAA and in cultured vascular smooth muscle cells (VSMC). Methods Experimental AAA was induced in C57BL/6 mice (males, 12 weeks old) by transient elastase perfusion of the aorta. Mice were randomly divided into control (vehicle, i.p.) and treatment (SOCS1 peptide, 3 mg/kg/day, i.p.) groups. Fourteen days after AAA induction, mice were sacrificed, and aorta segments were collected for histology (n=10/group) and mRNA and protein expression analysis (n=8/group). Results Compared to the AAA control group, SOCS1-treated mice exhibited a significant decrease in aortic diameter (68±6% vs. control; p<0.005) and aortic wall thickness, (67±3% vs. control; p<0.001). Histological analyses of aortic tissues showed a higher content of VSMC (α-actin) along with reduced leukocyte infiltration (macrophages, neutrophils and T-cells) and oxidative stress markers (superoxide anion and 8-hydroxyguanosine) in SOCS1-treated mice. SOCS1 therapy also attenuated the gene expression of inflammatory cytokines (CCL2, CCL5, TNF, IFNγ) and matrix metalloproteinases (MMP2, MMP9) in aortic lesions, and altered the expression levels of macrophage M1 (ArgII, iNOS) and M2 (ArgI, CD206) polarization markers. In vitro experiments in murine VSMC revealed that SOCS1 peptide prevented the expression of cytokines and chemokines induced by non-toxic dose of elastase (5 ug/ml, 24 hours). Effects of SOCS1 treatment were accompanied by a reduction in STAT1 and STAT3 phosphorylation and gene expression, both in AAA lesions and cultured VSMC. Conclusion Our results suggest that SOCS1 peptide presents protective effects in experimental AAA by suppressing JAK/STAT pathway-mediated inflammation. Acknowledgement/Funding MINECO-FEDER (SAF2015-63696-R), ISCII (FIS-FEDER PI17/01495), Spanish Society of Arteriosclerosis.

scholarly journals Long Noncoding RNAs CARMN, LUCAT1, SMILR, and MALAT1 in Thoracic Aortic Aneurysm: Validation of Biomarkers in Clinical Samples

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Vaiva Patamsytė ◽  
Giedrius Žukovas ◽  
Dovydas Gečys ◽  
Diana Žaliaduonytė ◽  
Povilas Jakuška ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Blood Plasma ◽  
Thoracic Aortic Aneurysm ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Clinical Samples ◽  
Aortic Tissue ◽  
Relative Expression ◽  
Clinical Patient ◽  
Diagnostic Potential

Background and Objectives. Thoracic aortic aneurysm (TAA) is a silent disease characterised by aortic wall expansion and vascular smooth muscle cell (VSMC) dedifferentiation from contractile to synthetic phenotype. Long noncoding RNAs (lncRNAs) involved in VSMC phenotypic regulation could be considered as potential diagnostic indicators and therapeutic targets of TAA. In vitro studies show that lncRNAs CARMN, LUCAT1, MALAT1, and SMILR are associated with the VSMC phenotypic state. Our aim was to test if these lncRNAs are dysregulated during TAA formation in clinical patient samples. Materials and Methods. Relative expression of lncRNAs CARMN, LUCAT1, SMILR, and MALAT1 was tested in clinical aortic tissue and blood plasma samples from TAA and non-TAA patients using the qRT-PCR method. The Mann–Whitney U test was used to compare ΔCt values between the study groups. ROC curve analysis was performed to evaluate the diagnostic value of plasma lncRNAs. Results. We found significantly reduced CARMN (p=0.033) and LUCAT1 (p=0.009) expression in aortic tissue samples from TAA patients. Relative expression of MALAT1 (p=0.117) and SMILR (p=0.610) did not differ in aortic tissue between the TAA and non-TAA groups. Expression of both LUCAT1 and SMILR was significantly decreased in TAA patients’ blood plasma compared to controls (p=0.018 and p=0.032, respectively). However, only LUCAT1 showed the ability to discriminate aneurysmal disease in patients’ blood plasma (AUC=0.654, 95%CI=0.534‐0.775, p=0.018). Conclusions. We have shown that the expression of lncRNAs CARMN and LUCAT1 is reduced in dilated aortic tissue and that the LUCAT1 and SMILR expression is lower in the blood plasma of TAA patients. Decreased LUCAT1 expression in TAA patients’ blood plasma may have diagnostic potential in discriminating patients with TAA.

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