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Molecular Fingerprint for Terminal Abdominal Aortic Aneurysm Disease.

Molecular Fingerprint for Terminal Abdominal Aortic Aneurysm Disease.
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Gäbel G, Northoff BH, Weinzierl I, Ludwig S, Hinterseher I, Wilfert W, Teupser D, Doderer SA, Bergert H, Schönleben F, Lindeman JHN, Holdt LM,


Gäbel G, Northoff BH, Weinzierl I, Ludwig S, Hinterseher I, Wilfert W, Teupser D, Doderer SA, Bergert H, Schönleben F, Lindeman JHN, Holdt LM, (click to view)

Gäbel G, Northoff BH, Weinzierl I, Ludwig S, Hinterseher I, Wilfert W, Teupser D, Doderer SA, Bergert H, Schönleben F, Lindeman JHN, Holdt LM,

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Journal of the American Heart Association 2017 11 306(12) pii e006798
Abstract
BACKGROUND
Clinical decision making in abdominal aortic aneurysms (AAA) relies completely on diameter. At this point, improved decision tools remain an unmet medical need. Our goal was to identify changes at the molecular level specifically leading up to AAA rupture.

METHODS AND RESULTS
Aortic wall tissue specimens were collected during open elective (eAAA; n=31) or emergency repair of ruptured AAA (rAAA; n=17), and gene expression was investigated using microarrays. Identified candidate genes were validated with quantitative real-time polymerase chain reaction in an independent sample set (eAAA: n=46; rAAA: n=18). Two gene sets were identified, 1 set containing 5 genes linked to terminal progression, that is, positively associated with progression of larger AAA, and with rupture (HILPDA, ANGPTL4, LOX, SRPX2, FCGBP), and a second set containing 5 genes exclusively upregulated in rAAA (ADAMTS9, STC1, GFPT2, GAL3ST4, CCL4L1). Genes in both sets essentially associated with processes related to impaired tissue remodeling, such as angiogenesis and adipogenesis. In gene expression experiments we were able to show that upregulated gene expression for identified candidate genes is unique for AAA. Functionally, the selected upregulated factors converge at processes coordinated by the canonical HIF-1α signaling pathway and are highly expressed in fibroblasts but not inflammatory cells of the aneurysmatic wall. Histological quantification of angiogenesis and exploration of the HIF-1α network in rAAA versus eAAA shows enhanced microvessel density but also clear activation of the HIF-1α network in rAAA.

CONCLUSIONS
Our study shows a specific molecular fingerprint for terminal AAA disease. These changes appear to converge at activation of HIF-1α signaling in mesenchymal cells. Aspects of this cascade might represent targets for rupture risk assessment.

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