scholarly journals Myeloid-Derived TSP1 (Thrombospondin-1) Contributes to Abdominal Aortic Aneurysm Through Suppressing Tissue Inhibitor of Metalloproteinases-1

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
Huan Yang ◽  
Ting Zhou ◽  
Christine M. Sorenson ◽  
Nader Sheibani ◽  
Bo Liu
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Inflammatory Cells ◽  
Matricellular Protein ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Tissue Inhibitor ◽  
Abdominal Aortic ◽  
Thrombospondin 1 ◽  
Inflammatory Macrophages

Objective: Abdominal aortic aneurysm is characterized by the progressive loss of aortic integrity and accumulation of inflammatory cells primarily macrophages. We previously reported that global deletion of matricellular protein TSP1 (thrombospondin-1) protects mice from aneurysm formation. The objective of the current study is to investigate the cellular and molecular mechanisms underlying TSP1’s action in aneurysm. Approach and Results: Using RNA fluorescent in situ hybridization, we identified macrophages being the major source of TSP1 in human and mouse aneurysmal tissues, accounting for over 70% of cells that actively expressed Thbs1 mRNA. Lack of TSP1 in macrophages decreased solution-based gelatinase activities by elevating TIMP1 (tissue inhibitor of metalloproteinases-1) without affecting the major MMPs (matrix metalloproteinases). Knocking down Timp1 restored the ability of Thbs1 − /− macrophages to invade matrix. Finally, we generated Thbs1 flox/flox mice and crossed them with Lyz2-cre mice. In the CaCl 2 -induced model of abdominal aortic aneurysm, lacking TSP1 in myeloid cells was sufficient to protect mice from aneurysm by reducing macrophage accumulation and preserving aortic integrity. Conclusions: TSP1 contributes to aneurysm pathogenesis, at least in part, by suppressing TIMP1 expression, which subsequently enables inflammatory macrophages to infiltrate vascular tissues.

scholarly journals Gene polymorphism -418 G/C of tissue inhibitor of metalloproteinases 2 is associated with abdominal aortic aneurysm

2015 ◽  
Vol 61 (5) ◽  
pp. 1114-1119 ◽  
Author(s):  
Joanna Mikołajczyk-Stecyna ◽  
Aleksandra Korcz ◽  
Marcin Gabriel ◽  
Katarzyna Pawlaczyk ◽  
Grzegorz Oszkinis ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Gene Polymorphism ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Tissue Inhibitor ◽  
Abdominal Aortic

scholarly journals High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice

2017 ◽  
Vol 131 (12) ◽  
pp. 1261-1281 ◽  
Author(s):  
Smriti Murali Krishna ◽  
Sai Wang Seto ◽  
Roby Jose ◽  
Jiaze Li ◽  
Joseph Moxon ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Ex Vivo ◽  
High Serum ◽  
Matricellular Protein ◽  
Body Tissues ◽  
Age Related ◽  
Abdominal Aortic ◽  
Thrombospondin 1

Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearman’s rho −0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19–0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1−/−ApoE−/−, n=20) and control mice (ApoE−/−, n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1−/− ApoE−/− mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1−/−ApoE−/− mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1−/−ApoE−/− mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1−/−ApoE−/− mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression.

Inflammatory Cells and Proteases in Abdominal Aortic Aneurysm and its Complications

2018 ◽  
Vol 19 (11) ◽  
pp. 1289-1296 ◽  
Author(s):  
Haiying Jiang ◽  
Takeshi Sasaki ◽  
Enze Jin ◽  
Masafumi Kuzuya ◽  
Xian Wu Cheng
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cells ◽  
Abdominal Aortic

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 Matricellular protein CCN3 mitigates abdominal aortic aneurysm

2016 ◽  
Vol 126 (4) ◽  
pp. 1282-1299 ◽  
Author(s):  
Chao Zhang ◽  
Dustin van der Voort ◽  
Hong Shi ◽  
Rongli Zhang ◽  
Yulan Qing ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Matricellular Protein ◽  
Abdominal Aortic

scholarly journals IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Hao Chai ◽  
ZhongHao Tao ◽  
YongChao Qi ◽  
HaoYu Qi ◽  
Wen Chen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Ang Ii ◽  
Elastin Degradation ◽  
Maximal Diameter ◽  
Abdominal Aortic ◽  
Primary Mouse

Abdominal aortic aneurysm (AAA) is a vascular disorder that is considered a chronic inflammatory disease. However, the precise molecular mechanisms involved in AAA have not been fully elucidated. Recently, significant progress has been made in understanding the function and mechanism of action of inhibitor of kappa B kinase epsilon (IKKε) in inflammatory and metabolic diseases. The angiotensin II- (Ang II-) induced or pharmacological inhibitors were established to test the effects of IKKε on AAA in vivo. After mice were continuously stimulated with Ang II for 28 days, morphologically, we found that knockout of IKKε reduced AAA formation and drastically reduced maximal diameter and severity. We also observed a decrease in elastin degradation and medial destruction, which were independent of systolic blood pressure or plasma cholesterol concentrations. Western blot analyses and immunohistochemical staining were carried out to measure IKKε expression in AAA tissues and cell lines. AAA phenotype of mice was measured by ultrasound and biochemical indexes. In zymography, immunohistology staining, immunofluorescence staining, and reactive oxygen species (ROS) analysis, TUNEL assay was used to examine the effects of IKKε on AAA progression in AAA mice. IKKε deficiency significantly inhibited inflammatory macrophage infiltration, matrix metalloproteinase (MMP) activity, ROS production, and vascular smooth muscle cell (VSMC) apoptosis. We used primary mouse aortic VSMC isolated from apolipoprotein E (Apoe) −/− and Apoe−/−IKKε−/− mice. Mechanistically, IKKε deficiency blunted the activation of the ERK1/2 pathway. The IKKε inhibitor, amlexanox, has the same impact in AAA. Our results demonstrate a critical role of IKKε in AAA formation induced by Ang II in Apoe−/− mice. Targeting IKKε may constitute a novel therapeutic strategy to prevent AAA progression.

scholarly journals Bioinformatics analysis of potential common molecular pathogenesis assumed by intracranial aneurysm, aortic aneurysm and aortic dissection

2021 ◽  
Author(s):  
Chao Zhao ◽  
Xinchun Cui ◽  
Guodong Liu ◽  
Jianlong Li ◽  
Jinxing Liu ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Intracranial Aneurysm ◽  
Molecular Mechanisms ◽  
Biological Processes ◽  
Network Analyses ◽  
Abdominal Aortic ◽  
Genetic Overlap ◽  
Pathogenesis Related

Abstract This study is intended to find possible pathogenesis-related genetic overlap and common molecular mechanisms of intracranial aneurysm, abdominal aortic aneurysm and aortic dissection. Three mRNA microarray datasets,GSE75436 of intracranial aneurysms, GSE7084 of abdominal aortic aneurysm and GSE52093 of aortic dissection were downloaded from Gene Expression Omnibus and detected in silico . DEGs of these three datasets screened through GEO2R, respectively . The overlapping genes were found by Venny mapping. Subsequently, Gene Ontology, Kyoto Encyclopedia of Genes and Genomespathway enrichment analysiswere performed using the DAVID database and protein-protein interaction network analyses were conducted by STRING and Cytoscape webpage tool to illustrate the molecular mechanisms in their pathogenesis and progression.This study identified 178 DEGs, including SMTN, MYH11, TAGLN, ACTG2, CNN1, MYLK, LMOD1, MYL9,VCL and ACTC1 in the the most significant module. Except for those confirmed biological processes, mesenchyme migration and platelet aggregation are common biological processes shared by genes in the most significant module and the hub genes. Focal adhesionssignaling pathway is highlighted in this analysis. The present study identified possible pathogenesis-related genetic overlap and common molecular mechanisms of intracranial aneurysm, abdominal aortic aneurysm and aortic dissection, which may contribute to their diagnosis, treatment and prognostic prediction with a systematic view.

Abstract 260: Identification of Micrornas Specifically Expressed in Isolated Cells of Human Abdominal Aortic Aneurysm

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Florence Pinet ◽  
Rafaelle Spear ◽  
David Hot ◽  
Bart Staels ◽  
Maggy Chwastyniak ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cells ◽  
The Elderly ◽  
M2 Macrophages ◽  
Isolated Cells ◽  
Human Mirnas ◽  
Specific Distribution ◽  
Abdominal Aortic ◽  
M1 And M2 Macrophages

Abdominal aortic aneurysm (AAA) is a vascular asymptomatic disease responsible for 4% of mortality in the elderly population. MicroRNAs (miRNA) have recently been shown to be potential biomarkers due to their stability in plasma. The aim of this study was to investigate the potentiality of miRNAS as biomarkers of AAA by identifying miRNAs specifically expressed in the key cells present in the human AAA tissue. The distribution of inflammatory cells such as smooth muscle cells (SMC), M1 and M2 macrophages, neutrophils, B and T lymphocytes and mast cells were located by immunohistochemistry in 20 human AAA biopsies, showing a specific distribution towards the aneurysmal aortic wall and the presence of adventitial tertiary lymphoid organs (ATLOs) in 10 samples. We isolated by laser microdissection (LMD) area enriched in aneurysmal SMC, M1 and M2 macrophages, and ATLOs and SMC from control aorta. RNA extracted from 2 samples of LMD-isolated cells was screened on human miRNAs microarray. Out of the 850 human miRNAs, more than 200 miRNAs were detected in LMD-isolated aneurysmal cells, with 164 detected in ATLOs, 49 in SMC, and 87 miRNAs in macrophages. We selected the 3 miRs with the highest expression for ATLOs and 10 miRs (based on their miR-29b levels) for SMC and macrophages for validation by qRT-PCR in LMD-isolated samples (n=4). We found that miR-15a-3p (0.1 fold) and miR-30a-5p (0.2 fold) were down-regulated and miR-489-3p up-regulated (2 fold) in ATLOs which was inversed for miR-489-3p in the whole aneurysmal aorta. Of the 10 miRNAs selected, six (miR-199a-3p and miR-451 upregulated and miR-24, miR-29a, miR-29b, and miR-29c downregulated) were modulated similarly in SMC and macrophages and whole aneurysmal aorta, except for miR-199-3p. Let-7f and miR-34a were similarly upregulated ed in both subtypes of macrophages and aneurysmal aorta. Expression in the plasma of AAA (n=24) compared to PAD (n=18) patients was significantly down-regulated for miR-15a-3p (p = 0.03) and miR-30a-5p (p = 0.04) and upregulated for let-7f (p=0.048) and miR-29b (p=0.035). In conclusion, this non-hypothesis driven screening of miRNAs expressed in isolated aneurysmal cells allowed to identify four miRNAs as potential AAA biomarkers.

Sign in / Sign up

Export Citation Format

Share Document