Novel Pathways in the Pathobiology of Human Abdominal Aortic Aneurysms

Abstract

Objectives: Abdominal aortic aneurysm (AAA), a dilatation of the infrarenal aorta, typically affects males >65 years. The pathobiological mechanisms of human AAA are poorly understood. The goal of this study was to identify novel pathways involved in the development of AAAs. Methods: A custom-designed ‘AAA-chip’ was used to assay 43 of the differentially expressed genes identified in a previously published microarray study between AAA (n = 15) and control (n = 15) infrarenal abdominal aorta. Protein analyses were performed on selected genes. Results: Altogether 38 of the 43 genes on the ‘AAA-chip’ showed significantly different expression. Novel validated genes in AAA pathobiology included ADCY7, ARL4C, BLNK, FOSB, GATM, LYZ, MFGE8, PRUNE2, PTPRC, SMTN, TMODI and TPM2. These genes represent a wide range of biological functions, such as calcium signaling, development and differentiation, as well as cell adhesion not previously implicated in AAA pathobiology. Protein analyses for GATM, CD4, CXCR4, BLNK, PLEK, LYZ, FOSB, DUSP6, ITGA5 and PTPRC confirmed the mRNA findings. Conclusion: The results provide new directions for future research into AAA pathogenesis to study the role of novel genes confirmed here. New treatments and diagnostic tools for AAA could potentially be identified by studying these novel pathways.

Role of Proinflammatory CD68 + Mannose Receptor − Macrophages in Peroxiredoxin-1 Expression and in Abdominal Aortic Aneurysms in Humans

“…Other studies have investigated cultured AAA cells from human patients. 8 The secretome, proteome, or transcriptome might also be good targets for identifying biomarkers, either from whole-aorta tissue [9][10][11][12][13] or from the AAA-separated layers. 14,15 However, because AAA is a complex disease, and aneurysmal tissue is similarly complex, proteomic analyses of whole-organ AAA tissue can hide cell-specific targets.…”

“…25 Two independent groups using proteomic analysis have discovered that peroxiredoxin-1 (PRDX-1) might be a biomarker for AAA. 8,12 More precisely, Lamblin et al 8 showed that PRDX-1 is expressed by monocyte-derived macrophages. Studying the 2 macrophage subtypes in human AAA might, therefore, improve our understanding of their role in this disease and help to identify potential biomarkers secreted by these cells into the blood circulation.…”

Analysis of <b><i>ADAM17</i></b> Polymorphisms and Susceptibility to Sporadic Abdominal Aortic Aneurysm

“…ADAMs 8, 9, 10, 12, 15 and 17 were found to be expressed in both AAA and control aorta [19], and ADAM17 (TACE) was upregulated in human AAA aortic specimens and was associated with chronic inflammation, increased neoangiogenesis and ECM disruption [9]. The role that ADAM17 plays in the inflammation and proteolytic degradation of ECM in the vessel wall markedly contributes to the formation and rupture of an AAA [5,6]. ADAM17 is capable of cleaving several other cell surface molecules, such as TNF-α, TNFR1 and TNFR2, as well as IL-6R and IL-1RII, which are considered to be involved in inflammatory processes of the vasculature [10].…”

“…Multiple characteristics of AAA pathogenesis involve chronic inflammation [2], autoimmunity, increased neoangiogenesis [3], enhanced oxidative stress [4], and degradation of the extracellular matrix (ECM) [5]; however, the precise mechanisms of AAA formation and progression remain elusive [6]. …”

The expression of inhibitor of nuclear factor kappa-B kinase epsilon (IKKe) in human aortic aneurysm

“…AA are char-acterised by the medial degeneration, and investigations of the pathogenesis of AA focus mainly on the effects of hypertension, age, and apoptotic pathway activation, which finally results in the apoptosis of smooth muscle cells and degradation of the extracellular matrix [11,15]. Hinterseher et al [4] showed that gene such as GATM, FOSB, ADCY7 and proteins such as CXCR4, PLEK, and GATM participated in the development of AA using a custom-designed "AA-chip", Western blot and immunohistochemical staining. However, the precise underlying aetiology of AA remains unclear.…”