Discovery of crucial cytokines associated with abdominal aortic aneurysm formation by protein array analysis

Abstract

As a common disease, abdominal aortic aneurysm (AAA) features permanently progressively dilated abdominal aorta. Various cytokines are implicated in AAA pathogenesis. Clarification of involved cytokines combined with functional analysis may provide new insights into AAA pathogenesis. Using a mouse model, this study analyzed the cytokine profiles in AAA. Cytokines were measured in AAA tissues of saline control or angiotensin II-treated ApoE−/− mice using an antibody array of 200 cytokines, cytokine receptors, and related proteins. Statistical analysis revealed that 21 of 200 proteins were differentially expressed in AAA. These differentially expressed proteins were subjected to function and pathway enrichment analysis, which revealed that leukocyte migration and positive regulation of cell adhesion were the most significant biological processes. Specific signaling pathways, including Janus kinase/signal transducers and activators of transcription and cytokine–cytokine receptor interaction, were prominent in Kyoto encyclopedia of genes and genomes pathway enrichment analysis. Importantly, our data identified cytokines which had not previously been illustrated in AAA pathogenic pathways. Bivariate correlation analysis between these cytokines and protease activity showed that granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein 1 g, cardiotrophin 1, milk fat globule-EGF factor 8 protein, interleukin 33, and periostin were positively correlated with matrix metalloprotease 1 (MMP-1), MMP-9, cathepsin B, and cathepsin L. G-CSF was positively correlated with cathepsin L. In conclusion, these results demonstrate that cytokine profile is significantly altered in AAA, and that the newly identified crucial cytokines may function potentially in AAA pathogenesis. Impact statement Various cytokines are known contributors to abdominal aortic aneurysm (AAA) pathologic processes, but the mechanisms underlying the pathogenesis remains unclear. We illustrated the altered cytokine profiles in AAA by high throughput antibody array of 200 cytokines, cytokine receptors and related proteins, as well as bioinformatics analysis of differentially expressed proteins in lesion tissues from AAA mice infused with angiotensin II. Functional analyses of differentially expressed cytokines showed clustering on cell migration and adhesion processes. More importantly, crucial cytokines whose association with AAA formation had not been established were identified. Significant correlations were found between these cytokines and protease activity. This study identifies several crucial markers for further researches on the molecular basis of AAA.

The mechanism and therapy of aortic aneurysms

“…In a mouse model of AA, cytokines change significantly. 186 We review several cytokines that are important in AA disease.…”

Akkermansia muciniphila Alters Gut Microbiota and Immune System to Improve Cardiovascular Diseases in Murine Model

“…AAA is the most commonly defined as having a maximum diameter of the abdominal aorta greater than 3 cm in anteriorly or cross-section, or having a focal dilation greater than 1.5 times the diameter of a normal adjacent artery segment ( Wang et al, 2018 ). The pathological manifestations of AAA in human and animal models showed obvious immune cell infiltration and upregulated expression of pro-inflammatory cytokines, suggesting that inflammation plays an important role in the formation of AAA ( Li Y. et al, 2019 ; Tsai and Xian, 2019 ). Functional enrichment analysis showed the level of granulocyte colony-stimulating factor (G-CSF), milk fat globule-EGF factor 8 protein (MFG-E8), macrophage inflammatory protein 1 g (MIP-1g), and cardiotrophin 1 (CT-1) were positively correlated with IL-33, periostin, matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-9 (MMP-9), cathepsin B (CTSB), and cathepsin L (CTSL) in AAA mice ( Li Y. et al, 2019 ).…”

“…The pathological manifestations of AAA in human and animal models showed obvious immune cell infiltration and upregulated expression of pro-inflammatory cytokines, suggesting that inflammation plays an important role in the formation of AAA ( Li Y. et al, 2019 ; Tsai and Xian, 2019 ). Functional enrichment analysis showed the level of granulocyte colony-stimulating factor (G-CSF), milk fat globule-EGF factor 8 protein (MFG-E8), macrophage inflammatory protein 1 g (MIP-1g), and cardiotrophin 1 (CT-1) were positively correlated with IL-33, periostin, matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-9 (MMP-9), cathepsin B (CTSB), and cathepsin L (CTSL) in AAA mice ( Li Y. et al, 2019 ). IL-33 is a pliotropic cytokine with multiple immunomodulatory effects ( Li J. et al, 2019 ).…”

The Role of Interleukin-6 Family Members in Cardiovascular Diseases

“…CT-1 can stimulate aortic endothelial cells to overproduce MMP-1, which leads to ECM degradation. These mechanisms are associated with the formation and progression of AAA ( 107 , 108 ).…”