Inhibition of CXCR2 alleviates the development of abdominal aortic aneurysm in Apo E-/- mice.

Bo Sun,Hongxia Wang,Yuexin Chen,Song Lai,Xu Zhang,Fangda Li,Wei Wang,Yuan Li,Yuehong Zheng,Bao Liu

doi:10.1590/acb360105

Abstract

ABSTRACTPurposeTo investigate the relationship between atherosclerotic abdominal aortic aneurysm (AAA) and CXC chemokine receptor type 2 (CXCR2).MethodsMouse AAA model was established by embedding angiotensin-II pump (1000 ng/kg/min) in ApoE-/- mice. Mice were received SB225002, a selective CXCR2 antagonist, for treatment. Blood pressure was recorded, and CXCR2+ macrophages were examined by flow cytometry analysis. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining was performed to detect cell apoptosis of abdominal aortic aneurysms. Macrophages were isolated from ApoE-/- mice and treated with Ang II and/or SB225002. Dihydroethidium staining was carried out to determine reactive oxygen species (ROS) activity. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the production of IL-1β and TNF-α. The corresponding gene expressions were measured using real-time polymerase chain reaction (PCR), western blot, and immunohistochemistry staining.ResultsWe found that Ang II activated the expression of CXCR2 in monocytes during the formation of AAA. Inhibition of CXCR2 significantly reduced the size of AAA, attenuated inflammation and phenotypic changes in blood vessels. Ang II-induced macrophages exhibited elevated ROS activity, and elevated levels of 1β and TNF-α, which were then partly abolished by SB225002.ConclusionsCXCR2 plays an important role in AAA, suggesting that inhibiting CXCR2 may be a new treatment for AAA.

Highlights

Abdominal aortic aneurysm (AAA) refers to the irreversible dilatation of the renal inferior abdominal aorta, whose dilated diameter is ≥ 3.0 cm, and the risk factors of AAA include old age, male, smoking, obesity, etc
CXC chemokine receptor type 2 (CXCR2)+ macrophages were up-regulated in abdominal aortic aneurysm animal model
The results showed that the mRNA and protein levels of CXCR2 were obviously increased after the vessels were infused with angiotensin II (Ang II) (Fig. 2a-b)

Summary

Introduction

Abdominal aortic aneurysm (AAA) refers to the irreversible dilatation of the renal inferior abdominal aorta, whose dilated diameter is ≥ 3.0 cm, and the risk factors of AAA include old age, male, smoking, obesity, etc. Study on human AAA tissue showed that the number of inflammatory cells infiltrated by the outer membrane, mainly macrophages, increased with the gradual widening of AAA diameter[6]. These cells can directly or indirectly induce the proliferation, activation, differentiation, and apoptosis of other cells in the vascular wall by releasing proteolytic enzymes, such as cytokines and oxidationderived free radicals, to regulate the remodeling of the vascular wall[7]

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Discussion

Conclusion