Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm

Abstract

We sought to characterize temporal gene expression changes in the murine angiotensin II (ANG II)-ApoE-/- model of abdominal aortic aneurysm (AAA). Aortic ultrasound measurements were obtained over the 28-day time-course. Harvested suprarenal aortic segments were evaluated with whole genome expression profiling at 7, 14, and 28 days using the Agilent Whole Mouse Genome microarray platform and Statistical Analysis of Microarrays at a false discovery rate of <1%. A group of angiotensin-treated mice experienced contained rupture (CR) within 7 days and were analyzed separately. Progressive aortic dilatation occurred throughout the treatment period. However, the numerous early expression differences between ANG II-treated and control were not sustained over time. Ontologic analysis revealed widespread upregulation of inflammatory, immune, and matrix remodeling genes with ANG II treatment, among other pathways such as apoptosis, cell cycling, angiogenesis, and p53 signaling. CR aneurysms displayed significant decreases in TGF-β/BMP-pathway signaling, MAPK signaling, and ErbB signaling genes vs. non-CR/ANG II-treated samples. We also performed literature-based network analysis, extracting numerous highly interconnected genes associated with aneurysm development such as Spp1, Myd88, Adam17 and Lox. 1) ANG II treatment induces extensive early differential expression changes involving abundant signaling pathways in the suprarenal abdominal aorta, particularly wide-ranging increases in inflammatory genes with aneurysm development. 2) These gene expression changes appear to dissipate with time despite continued growth, suggesting that early changes in gene expression influence disease progression in this AAA model, and that the aortic tissue adapts to prolonged ANG II infusion. 3) Network analysis identified nexus genes that may constitute aneurysm biomarkers or therapeutic targets.

miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development

“…Ontologic pathway enrichment of significant genes was performed as previously described 24 . Briefly, numerous genes differentiated scr-miR-treated PPE-induced AAA from scr-miR-treated sham-control aorta.…”

Involvement of the renin–angiotensin system in abdominal and thoracic aortic aneurysms

“…These analyses have demonstrated that AngII increases the abundance of a wide spectrum of genes for inflammation, immunity, matrix degeneration, apoptosis, cell cycling, angiogenesis and signalling pathways [46,47]. Another noteworthy attribute is that these analyses reveal that the pattern of gene abundance differs widely during progressive intervals of AngII infusion.…”

“…Recent transcriptional profiling and network analyses of mouse AngII-induced AAAs have provided comprehensive information regarding this aneurysmal disease [46,47]. These analyses have demonstrated that AngII increases the abundance of a wide spectrum of genes for inflammation, immunity, matrix degeneration, apoptosis, cell cycling, angiogenesis and signalling pathways [46,47].…”

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

“…EGFR has been implicated in various vascular disorders including hypertension (252,253) and the development and progression of abdominal aortic aneurysms (523). Treatment of ANG II-infused mice with erlotinib attenuates vascular hypertrophy and perivascular fibrosis independent of alterations in blood pressure (536).…”