Gene Expression Study in Positron Emission Tomography-Positive Abdominal Aortic Aneurysms Identifies CCL18 as a Potential Biomarker for Rupture Risk

Abstract

Rupture of abdominal aortic aneurysm (AAA) is a cause of significant mortality and morbidity in aging populations. Uptake of 18-fluorodeoxyglucose (FDG) detected by positron emission tomography (PET) is observed in the wall of 12% of AAA (A+), with most of them being symptomatic. We previously showed that the metabolically active areas displayed adventitial inflammation, medial degeneration and molecular alterations prefacing wall rupture. The aim of this study was to identify new factors predictive of rupture. Transcriptomic analyses were performed in the media and adventitia layers from three types of samples: AAA without FDG uptake (A0) and with FDG uptake (A+), both at the positive spot (A+ Pos ) and at a paired distant negative site (A+ Neg ) of the same aneurysm. Follow-up studies included reverse-transcriptase-polymerase chain reaction (RT-PCR), immunohistochemical staining and enzyme-linked immunosorbent assay (ELISA). A large number of genes, including matrix metalloproteinases, collagens and cytokines as well as genes involved in osteochondral development, were differentially expressed in the A+ Pos compared with A+ Neg . Moreover, a series of genes (notably CCL18) was differentially expressed both in the A+ Neg and A+ Pos compared with the A0. A significant increase of CCL18 was also found at the protein level in the aortic wall and in peripheral blood of A+ patients compared with A0. In conclusion, new factors, including CCL18, involved in the progression of AAA and, potentially, in their rupture were identified by a genome-wide analysis of PET-positive and -negative human aortic tissue samples. Further work is needed to study their role in AAA destabilization and weakening.

Circulating microRNAs signature correlates with positive [18F]fluorodeoxyglucose-positron emission tomography in patients with abdominal aortic aneurysm

“…To consolidate their role, we compared the validated and potential targets of these three miRNAs with the set of upregulated genes identified in a previous transcriptomic analysis of the aneurysmal wall from Aþ patients. 7 No common genes were obtained for the miR-99b-5pm whereas w30 targets genes were found to be modulated in our transcriptomic study for miR-125b-5p and miR-204-5p (Fig 5). 7,21 Runt-related transcription factor 2 (RUNX2), a transcription factor involved in osteochondral development, is a validated target of miR-204-5p.…”

“…The 7 The network was generated using Cytoscape software. 21 discriminating power of the identified miRNAs, as determined by ROC curve analyses, suggests their potential to identify unstable aneurysms in AAA patients, and miR-125b-5p seems the most powerful based on the ROC results (AUC ¼ 0.80; P < .0001).…”

“…20 The predicted targets for miR-99b-5p, miR-125b-5p, and miR-204-5p were compared with the list of modulated genes in the Aþ pos site compared with the Aþ neg site determined in our previous transcriptomic study. 7 Statistical analysis. Results are expressed as the median with the interquartile range (25-75 percentile) and considered to be significant at the 5% critical level (P < .05) by using the Mann-Whitney U test for unpaired samples or the Wilcoxon test for paired samples.…”

“…[5][6][7][8] In the same context, English et al 9 demonstrated a relationship between a positive FDG signal and rupture of AAA in an experimental animal model. A challenging aspect of AAA monitoring is the lack of reliable biomarkers reflecting the progression of aneurysm and the risk of rupture.…”

“…In a previous study, we used transcriptomic analysis to identify a set of genes modulated in this FDGþ uptake site. 7 In the present study, this set of genes was compared with the predicted target genes of the modulated miRNAs to identify relevant signaling pathways.…”