Abstract 19235: Infiltrating Macrophage-Derived Angiopoietin-Like Protein2 (Angptl2) Accelerates Abdominal Aortic Aneurysm by Inducing Chronic Inflammation and ECM Degradation
Abdominal Aortic Aneurysm (AAA) is characterized by aneurysmal morphological changes with low-grade chronic inflammation of atherosclerotic aortic walls. However, molecular mechanism has not been elucidated well. We recently reported that Angptl2 mediates various chronic inflammatory conditions, such as rheumatoid arthritis, dermatomyositis, cancer, and obesity-related metabolic disorder. In this study, we examined whether Angptl2 contributes to the pathogenesis of AAA formation. Firstly, we found expression of Angptl2 and pro-inflammatory cytokines mRNA in aneurysmal lesion of AAA patients were significantly increased compared to the non-dilating lesion. Angptl2 protein was abundantly expressed in infiltrating macrophages but not expressed in other inflammatory cells. We next examined whether Angptl2 deficiency affects the AAA formation in Angptl2-knockout (KO) mice. Interestingly, on day 28 after surgery, the sizes of AAA in Angptl2 KO mice were significantly decreased compared to wild-type mice (p<0.01). And expression of TNF-α, IL-1β, IL-6 and MMP-9 mRNAs in tissues from the aortic wall of CaCl2-treated Angptl2 KO mice was markedly decreased compared with that seen in wild-type mice. To identify the culprit cells secreting Angptl2 in AAA lesion, we transplanted bone marrow (BM) cells from Angptl2 KO mice or littermate wild-type controls into lethally irradiated wild-type recipients. The sizes of AAA in the recipients of Angptl2-deficient BM cells were significantly attenuated compared to those in the recipients of wild-type control BM cells (p<0.01). Finally, to investigate whether macrophage-derived Angptl2 could alter expression levels of proinflammatory cytokines and MMP-9 in macrophages, we analyzed expression of pro-inflammatory cytokines in thioglycollate(TGC)-induced peritoneal inflammatory macrophages. Significant decreases in TNF-α, IL-1β, IL-6 and MMP-9 expression were observed in macrophages from Angptl2 KO mice compared with similarly treated wild-type mice. These results suggest that infiltrating macrophage-derived Angptl2 promotes expression of proinflammatory cytokines and MMP-9 in these cells, resulting in progression of AAA pathogenesis.
- © 2012 by American Heart Association, Inc.