Altered Patterns of Gene Expression Specific to Thoracic Aortic Aneurysms

Thoracic aortic aneurysms (TAAs) result from maladaptive remodeling of the vascular extracellular matrix (ECM). In addition to structural protein changes, resident cellular profiles are altered leaving the fibroblast as the predominant cell type within the vascular wall. The present study tests the hypothesis that fibroblast phenotype is also altered during TAA development. Primary murine aortic fibroblasts were isolated from normal (n=4) and TAA aortas (n=3; 4-wks post-induction; topical 0.5M CaCl 2 15 min) by the outgrowth method. Cultures were established and passages 3–5 were used for gene expression profiling in the absence of stimulation. Relative expression of 30 genes (MMPs, ECM proteins, transcription factors) normalized to 4 house keeping genes was measured by quantitative real-time PCR. Genes displaying a minimum 2-fold increase/decrease or genes with significantly different normalized Ct values (t-test, TAA vs. control; p<0.05) were considered to have altered expression Steady state gene expression of 4-wk TAA versus normal fibroblasts revealed elevated expression of Mmp2, Mmp11, Mmp15, Col1a1, Col1a2, Col3a1, Eln, Lamb2, Fn1, Fbn2, Spp1, Sparc, Fos, and Fosb, and decreased expression of Mmp3, Timp3, Ltbp1, Sp1, and Junb ( Figure ). This study demonstrates for the first time that isolated aortic fibroblasts from 4-wk TAAs possess a unique gene expression profile as compared to normal fibroblasts. This suggests they have undergone a stable phenotypic change, which may be the result of a clonal expansion of a subset of cells, and may play a significant role in TAA development through the enhancement of ECM proteolysis.

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Targeted gene expression analyses and immunohistology suggest a pro-proliferative state in tricuspid aortic valve-, and senescence and viral infections in bicuspid aortic valve-associated thoracic aortic aneurysms

Atherosclerosis ◽

10.1016/j.atherosclerosis.2018.02.007 ◽

2018 ◽

Vol 271 ◽

pp. 111-119 ◽

Cited By ~ 9

Author(s):

Stefan Blunder ◽

Barbara Messner ◽

Bernhard Scharinger ◽

Christian Doppler ◽

Iris Zeller ◽

...

Keyword(s):

Gene Expression ◽

Aortic Valve ◽

Bicuspid Aortic Valve ◽

Viral Infections ◽

Aortic Aneurysms ◽

Thoracic Aortic Aneurysms ◽

Tricuspid Aortic Valve ◽

Gene Expression Analyses ◽

Targeted Gene Expression

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Integrated analysis of immunocyte infiltration and differential gene expression in tricuspid aortic valve-associated thoracic aortic aneurysms

Annals of Translational Medicine ◽

10.21037/atm.2020.03.05 ◽

2020 ◽

Vol 8 (6) ◽

pp. 285-285

Author(s):

Xiaoping Fan ◽

Jihai Peng ◽

Liming Lei ◽

Jie He ◽

Jinsong Huang ◽

...

Keyword(s):

Gene Expression ◽

Aortic Valve ◽

Differential Gene Expression ◽

Aortic Aneurysms ◽

Integrated Analysis ◽

Thoracic Aortic Aneurysms ◽

Tricuspid Aortic Valve ◽

Differential Gene

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Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00178.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. H103-H113 ◽

Cited By ~ 8

Author(s):

Jungsil Kim ◽

Jesse D. Procknow ◽

Hiromi Yanagisawa ◽

Jessica E. Wagenseil

Keyword(s):

Gene Expression ◽

Matrix Protein ◽

Mechanical Response ◽

Aortic Aneurysms ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Newborn Mice ◽

Thoracic Aortic Aneurysms ◽

Neutrophil Collagenase

Fibulin-4 is an extracellular matrix protein that is essential for proper assembly of arterial elastic fibers. Mutations in fibulin-4 cause cutis laxa with thoracic aortic aneurysms (TAAs). Sixty percent of TAAs occur in the ascending aorta (AA). Newborn mice lacking fibulin-4 ( Fbln4−/−) have aneurysms in the AA, but narrowing in the descending aorta (DA), and are a unique model to investigate locational differences in aneurysm susceptibility. We measured mechanical behavior and gene expression of AA and DA segments in newborn Fbln4−/− and Fbln4+/+ mice. Fbln4−/− AA has increased diameters compared with Fbln4+/+ AA and Fbln4−/− DA at most applied pressures, confirming genotypic and locational specificity of the aneurysm phenotype. When diameter compliance and tangent modulus were calculated from the mechanical data, we found few significant differences between genotypes, suggesting that the mechanical response to incremental diameter changes is similar, despite the fragmented elastic fibers in Fbln4−/− aortas. Fbln4−/− aortas showed a trend toward increased circumferential stretch, which may be transmitted to smooth muscle cells (SMCs) in the wall. Gene expression data suggest activation of pathways for SMC proliferation and inflammation in Fbln4−/− aortas compared with Fbln4+/+. Additional genes in both pathways, as well as matrix metalloprotease-8 ( Mmp8), are upregulated specifically in Fbln4−/− AA compared with Fbln4+/+ AA and Fbln4−/− DA. Mmp8 is a neutrophil collagenase that targets type 1 collagen, and upregulation may be necessary to allow diameter expansion in Fbln4−/− AA. Our results provide molecular and mechanical targets for further investigation in aneurysm pathogenesis.

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Altered Pattern of Gene Expression in Thoracic Aortic Aneurysms in Patients with Trileaflet and Bileaflet Aortic Valve: A Pilot Study Using Affymetrix Gene Chips

The FASEB Journal ◽

10.1096/fasebj.20.5.a1074 ◽

2006 ◽

Vol 20 (5) ◽

Author(s):

Ramanath Majumdar ◽

Takieddine Sami ◽

Marineh Yagubyan ◽

Gobinda Sarkar ◽

Mark Bolander ◽

...

Keyword(s):

Gene Expression ◽

Pilot Study ◽

Aortic Valve ◽

Aortic Aneurysms ◽

Thoracic Aortic Aneurysms ◽

Gene Chips

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Integration of Gene-Expression Profiles and Pathway Analysis in Ascending Thoracic Aortic Aneurysms

Annals of Vascular Surgery ◽

10.1016/j.avsg.2010.01.007 ◽

2010 ◽

Vol 24 (4) ◽

pp. 538-549 ◽

Cited By ~ 6

Author(s):

Jae Hyun Kim ◽

Chan-Young Na ◽

Si Young Choi ◽

Hwan Wook Kim ◽

Young Du Kim ◽

...

Keyword(s):

Gene Expression ◽

Pathway Analysis ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Aortic Aneurysms ◽

Thoracic Aortic Aneurysms

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Strategies to Manage Paraplegia Risk After Endovascular Stent Repair of Descending Thoracic Aortic Aneurysms

Yearbook of Vascular Surgery ◽

10.1016/s0749-4041(08)70484-6 ◽

2007 ◽

Vol 2007 ◽

pp. 186-187

Author(s):

K. Kasirajan

Keyword(s):

Aortic Aneurysms ◽

Endovascular Stent ◽

Thoracic Aortic Aneurysms

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Cannulation of the Ascending Aorta in Left Thoracotomy for Thoracic Aortic Aneurysms

The Heart Surgery Forum ◽

10.1532/hsf98.20041167 ◽

2007 ◽

Vol 10 (1) ◽

pp. E81-E83 ◽

Cited By ~ 1

Author(s):

Riza Turkoz ◽

Oner Gulcan ◽

Orhan Demirturk ◽

Ayda Turkoz

Keyword(s):

Ascending Aorta ◽

Aortic Aneurysms ◽

Left Thoracotomy ◽

Thoracic Aortic Aneurysms

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Epigenetic Profiling Identifies Novel Genes for Ascending Aortic Aneurysm Formation with Bicuspid Aortic Valves

The Heart Surgery Forum ◽

10.1532/hsf.1247 ◽

2015 ◽

Vol 18 (4) ◽

pp. 134 ◽

Cited By ~ 12

Author(s):

Asad A Shah

Keyword(s):

Gene Expression ◽

Aortic Aneurysm ◽

Methylation Status ◽

Aortic Aneurysms ◽

Aortic Valves ◽

Ascending Aortic Aneurysm ◽

Novel Genes ◽

Aneurysm Formation ◽

Aortic Replacement ◽

Bicuspid Aortic Valves

Background: Bicuspid aortic valves predispose to ascending aortic aneurysms, but the mechanisms underlying this aortopathy remain incompletely characterized. We sought to identify epigenetic pathways predisposing to aneurysm formation in bicuspid patients.Methods: Ascending aortic aneurysm tissue samples were collected at the time of aortic replacement in subjects with bicuspid and trileaflet aortic valves. Genome-wide DNA methylation status was determined on DNA from tissue using the Illumina 450K methylation chip, and gene expression was profiled on the same samples using Illumina Whole-Genome DASL arrays. Gene methylation and expression were compared between bicuspid and trileaflet individuals using an unadjusted Wilcoxon rank sum test. Results: Twenty-seven probes in 9 genes showed significant differential methylation and expression (P<5.5x10-4). The top gene was protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which was hypermethylated (delta beta range: +15.4 to +16.0%) and underexpressed (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10-5) in bicuspid patients, as compared to tricuspid patients. Numerous genes involved in cardiovascular development were also differentially methylated, but not differentially expressed, including ACTA2 (4 probes, delta beta range: -10.0 to -22.9%), which when mutated causes the syndrome of familial thoracic aortic aneurysms and dissectionsConclusions: Using an integrated, unbiased genomic approach, we have identified novel genes associated with ascending aortic aneurysms in patients with bicuspid aortic valves, modulated through epigenetic mechanisms. The top gene was PTPN22, which is involved in T-cell receptor signaling and associated with various immune disorders. These differences highlight novel potential mechanisms of aneurysm development in the bicuspid population.

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