The Molecular Mechanism Of Chemokine Receptor CXCR2 In Promoting The Formation Of Abdominal Aortic Aneurysm And Changes Of Serum Angiopoietin-related Growth Factor In Abdominal Aortic Aneurysm

Background and Objective:Abdominal aortic aneurysm (AAA) is a leading cause of sudden death in aging men. The AAA rupture causes a mortality rate of 60% to 80%. Many pathological progresses including inflammation, destruction of collagen and elastic fibers, alteration of SMC quantity and quality, and and angiogenesis contribute to the AAA occurance. Among the numerous pathophysiologic mechanisms, macrophage-mediated inflammation plays pivotal role in the progression of AAA. Activated by several cytokines, the CXC chemokine receptor CXCR2 plays a critical role in triggering arrest and chemotaxis of monocytes and other inflammatory cells and is involved in advanced atherosclerosis and other vascular diseases. However, the underlying mechanisms of how CXCR2 activation could recruit macrophage to infiltrate the abdominal aorta, induce the activation of oxidative stress and promote the synthesis and secretion of the matrix metalloproteinases (MMPs), remain unknown.To determine whether CXCR2 is involved in the progression of AAA, we have used the specific CXCR2 antagonist SB265610 to block the chemokine signalling induced by Ang Ⅱ in ApoE-/-mice. Moveover, we investigate the changes and value ofplasma angiopo ietin-related growth factor (AGF) in abdominal aortic aneurysm (AAA).Materials and methods:(1) We induced the AAA in ApoE-/-mice by angiotensin Ⅱ (Ang Ⅱ) infusion (1,000 ng/min/kg).(2)CXCR2 was inhibited by intraperitoneal injection of SB265610 (2mg/kg·d). Here, the mice were divided into four groups:Saline, SB265610, Ang Ⅱ, and Ang Ⅱ+sb265610. The appearance of the aorta was monitored by B-mode ultrasound, the blood pressure was measured through tail-cuff, and the gross anatomy morphology was pictured in each group. Aortic structural remodeling and inflammation were observed by HE staining, Elastin staining and immunohistochemical staining. The inflammatory cells infiltration in the aorta and the circulating inflammatory cells were analysed by cytometry. The mRNA expression levels of specific cytokines were detected by PCR analysis. The oxidative stress activation of the aorta was determined by DHE staining. The expression and activaty of metalloproteinase were determined by Western Blot, gelatin zymography and immunohisto chemical staining.Results:1. AAA model was successfully established by continuous infusion of Ang Ⅱ on the ApoE-/- mice.2. SB265610 injection significantly reduced Ang Ⅱ-induced AAA formation in mice (the incidence and diameter) by inhibiting CXCR2.3. The recruitment of macrophage, the expression and activity of matrix metalloproteinase within the arterial wall, the vascular remodeling and degradation of elastic fibers, and the oxidative stress activation within the vessel wall induced by Ang II-infusion were all inhibited by SB265610 injection.4. This study demonstrate that plasma AGF is highly expressed in AAA. Higher serum AGF level is associates with larger AAA. Detection of plasma AGF may be reliable for identifying the presence of AAA.Conclusion:We have found that blockade of CXCR2 could attenuate development of AAA by reducing the local inflammation. The infiltration of macrophage, the synthesis and secretion of MMPs, increased MMP activity and oxidative stress activation were all inhibited by SB265610 injection. In this way, we revealed the precise mechanisms of how CXCR2 promoted the AAA progression, and found a potential target for future strategies designed to combat AAA. What’s more, we demonstrated that plasma AGF was highly expressed in AAA and detection of plasma AGF could be reliable for identifying the presence of AAA.