CXCL8 hyper-signaling in the aortic abdominal aneurysm


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Abstract

HighlightsAbdominal Aortic Aneurysmal disease is associated with CXCL8 hyper expression.The CXCL-8 receptors CXCR1 and -2 are abundantly expression in the aneurysm wall.Histology for phospho-ERK and PKCΔ/φ, and gene expression profiling show exaggerated CXCL8 signaling in abdominal aortic aneurysmal disease.Interference with CXCL8 signaling through a DF2156, an oral CXCR1/2 antagonist prevented aneurysm formation in the elastase model, an established model for aneurysmal disease.There are indications for elevated CXCL8 levels in abdominal aortic aneurysm disease (AAA).CXCL8 is concurrently involved in neutrophil-mediated inflammation and angiogenesis, two prominent and distinctive characteristics of AAA. As such we considered an evaluation of a role for CXCL8 in AAA progression relevant.ELISA’s, real time PCR and array analysis were used to explore CXCL8 signaling in AAA wall samples. A role for CXCL8 in AAA disease was tested through the oral CXCR1/2 antagonist DF2156A in the elastase model of AAA disease.There is an extreme disparity in aortic wall CXCL8 content between AAA and aortic atherosclerotic disease (median [IQR] aortic wall CXCL8 content: 425 [141–1261] (AAA) vs. 23 [2.8–89] (atherosclerotic aorta) μg/g protein (P < 1 · 10−14)), and abundant expression of the CXCR1 and 2 receptors in AAA. Array analysis followed by pathway analysis showed that CXCL8 hyper-expression in AAA is followed increased by IL-8 signaling (Z-score for AAA vs. atherosclerotic control: 2.97, p < 0.0001).Interference with CXCL8 signaling through DF2156A fully abrogated AAA formation and prevented matrix degradation in the murine elastase model of AAA disease (p < 0.001).CXCL8-signaling is a prominent and distinctive feature of AAA, interference with the pathway constitutes a promising target for medical stabilization of AAA.

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