Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms

Lenk, Guy M.; Tromp, Gerard; Weinsheimer, Shantel; Gatalica, Zoran; Berguer, Ramón; Kuivaniemi, Helena

doi:10.1186/1471-2164-8-237

Cited by 155 publications

(267 citation statements)

References 62 publications

(60 reference statements)

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“…41 Moreover, the expression of TEAD3 and TEAD4 are both suppressed in the wall of the aorta of aortic aneurysm patients compared to healthy controls. 42 Thus, these TEAD factors were strong candidates for mediating TGF-β-dependent gene expression at the 9p21.3 locus in HAoSMCs. TGF-β is known to induce p16 and p15 expression to mediate cellular senescence and control cellular proliferation.…”

Section: Discussionmentioning

confidence: 93%

9p21.3 Coronary Artery Disease Risk Variants Disrupt TEAD Transcription Factor–Dependent Transforming Growth Factor β Regulation of p16 Expression in Human Aortic Smooth Muscle Cells

et al. 2015

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Background— The mechanism whereby the 9p21.3 locus confers risk for coronary artery disease remains incompletely understood. Risk alleles are associated with reduced expression of the cell cycle suppressor genes CDKN2A (p16 and p14) and CDKN2B (p15) and increased vascular smooth muscle cell proliferation. We asked whether risk alleles disrupt transcription factor binding to account for this effect. Methods and Results— A bioinformatic screen was used to predict which of 59 single nucleotide polymorphisms at the 9p21.3 locus disrupt (or create) transcription factor binding sites. Electrophoretic mobility shift and luciferase reporter assays examined the binding and functionality of the predicted regulatory sequences. Primary human aortic smooth muscle cells (HAoSMCs) were genotyped for 9p21.3, and HAoSMCs homozygous for the risk allele showed reduced p15 and p16 levels and increased proliferation. rs10811656 and rs4977757 disrupted functional TEF-1 TEC1 AbaA domain (TEAD) transcription factor binding sites. TEAD3 and TEAD4 overexpression induced p16 in HAoSMCs homozygous for the nonrisk allele, but not for the risk allele. Transforming growth factor β, known to activate p16 and also to interact with TEAD factors, failed to induce p16 or to inhibit proliferation of HAoSMCs homozygous for the risk allele. Knockdown of TEAD3 blocked transforming growth factor β–induced p16 mRNA and protein expression, and dual knockdown of TEAD3 and TEAD4 markedly reduced p16 expression in heterozygous HAoSMCs. Conclusions— Here, we identify a novel mechanism whereby sequences at the 9p21.3 risk locus disrupt TEAD factor binding and TEAD3-dependent transforming growth factor β induction of p16 in HAoSMCs. This mechanism accounts, in part, for the 9p21.3 coronary artery disease risk.

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Section: Discussionmentioning

confidence: 93%

9p21.3 Coronary Artery Disease Risk Variants Disrupt TEAD Transcription Factor–Dependent Transforming Growth Factor β Regulation of p16 Expression in Human Aortic Smooth Muscle Cells

et al. 2015

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“…Analyzing the results of such profiles generated for AAA tissues showed an overrepresentation of biological pathways involved in immune response, 84 providing further evidence that AAA is an immunologic disease.…”

Section: Global Gene Expression Profiles Of Aaa Tissue Reveal a Signimentioning

confidence: 87%

Aortic Aneurysms

2008

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“…Lenk et al 40 demonstrated that regulation of the actin cytoskeleton, focal adhesion, ECM-receptor, immune response, and inflammatory pathways was involved in the pathogenesis of AAAs. Cell communication has also been previously linked to the pathogenesis of AAAs.…”

Section: Shi Et Al Genomics Of Human Intracranial Aneurysmsmentioning

confidence: 99%

Genomics of Human Intracranial Aneurysm Wall

Shi

Awad

Jafari

et al. 2009

Stroke

107

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Background and Purpose-The pathogenesis of intracranial aneurysms (IAs) remains elusive. Most studies have focused on individual genes, or a few interrelated genes or products, at a time in human IA. However, a broad view of pathologic mechanisms has not been investigated by identifying pathogenic genes and their interaction in networks. Our study aimed to analyze global gene expression patterns in the IA wall. Methods-To our knowledge, our group was the first to perform Illumina microarray analysis on human IA via comparison of aneurysm wall and superficial temporal artery tissues from 6 consecutive patients. We adopted stringent statistical criteria to the individual genes; genes with a false discovery rate Ͻ0.01 and Ͼ2-fold change were selected as differentially expressed. To identify the overrepresented biologic pathways with the differentially expressed genes, we performed hypergeometric testing of the genes selected by relaxed criteria of PϽ0.01 and fold change Ͼ1.5. Results-There are 326 distinct differentially expressed genes between IA and superficial temporal artery tissues (Ͼ2-fold change) with a false discovery rate Ͻ0.01. Analysis of the Kyoto Encyclopedia of Genes and Genomes pathways revealed the most impacted functional pathways: focal adhesion, extracellular matrix receptor interaction, and cell communication. Analysis of the Gene Ontology also supported the involvement of another 2 potentially important pathways: inflammatory response and apoptosis. Conclusions-The differentially expressed genes in the aneurysm wall may shed light on aneurysm pathobiology and provide novel targets for therapeutic intervention. These data will help generate hypotheses for future studies. (Stroke.

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Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms

Cited by 155 publications

References 62 publications

9p21.3 Coronary Artery Disease Risk Variants Disrupt TEAD Transcription Factor–Dependent Transforming Growth Factor β Regulation of p16 Expression in Human Aortic Smooth Muscle Cells

9p21.3 Coronary Artery Disease Risk Variants Disrupt TEAD Transcription Factor–Dependent Transforming Growth Factor β Regulation of p16 Expression in Human Aortic Smooth Muscle Cells

Aortic Aneurysms

Genomics of Human Intracranial Aneurysm Wall

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