CXCR6/CXCL16 AXIS IS INVOLVED IN MONONUCLEAR CELL ADHESION INDUCED BY ANGIOTENSIN II, POTENTIAL IMPLICATION IN ABDOMINAL AORTIC ANEURYSM (AAA) FORMATION?
Maria J. Sanz, Ph.D., Faculty of Medicine, University of Valencia, Valencia, Spain
Background and Objectives: Abdominal aortic aneurysm (AAA) is a degenerative disease of the aorta that mainly affects elderly population over the age of 65. Nowadays the pathways involved in its onset and progression remain unknown and angiotensin-II (Ang-II) has been widely implicated. Therefore, the potential link between CXCR6/CXCL16 axis in AAA was investigated.
Methods and Results: Apolipoprotein E-deficient mice (apoE-/-) were subjected or not to a high-fat diet and infused with Ang-II (500 ng/kg/min) for 28 days. Some of the animals were daily treated with losartan at 10 or 30 mg/kg/day. Flow cytometry and immunofluorescence were used to determine CXCL16 expression on human umbilical vein or artery endothelial cells (HUVEC and HUAEC, respectively). Parallel-plate flow chamber assay was employed to evaluate leukocyte adhesion to Ang-II (1 microM)-stimulated human endothelium. Mice subjected to a high-fat diet and infused with Ang-II showed higher incidence of AAA, increased macrophage, CD3+ lymphocyte and CXCR6+ cell infiltration and enhanced neovascularization than unchallenged animals. These effects were accompanied by increased MCP-1/CCL2, CXCL16, CXCR6 and VEGF mRNA expression within the lesion. These events were reduced when losartan was administered at 30 but not at 10 mg/kg/day. When HUVEC and HUAEC were stimulated with 1 microM Ang-II (24h), a significant increase in CXCL16 expression was detected by flow cytometry and immunofluorescence. However, neutralization of CXCL16 activity only significantly inhibited Ang-II-induced mononuclear leukocyte-HUAEC interaction by 49% without affecting their interaction with HUVEC. Ang-II-induced CXCL16 expression was found to be dependent on Nox5 expression and subsequent RhoA/p38-MAPK/NFkB activation. Conclusion: These results suggest that the CXCR6/CXCL16 axis could constitute a new therapeutic strategy in the treatment of cardiovascular diseases associated with activation of the renin-angiotensin system (RAS).