The role of monocytic thrombomodulin in abdominal aortic aneurysm formation

• Main Authors: Min-HuaCheng, 成敏華
• Other Authors: Hua-Lin Wu
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/69g3bu

碩士 === 國立成功大學 === 生物化學暨分子生物學研究所 === 102 === Thrombomodulin (TM) is a transmembrane glycoprotein widely expressed on many cell types, such as endothelial cells and monocytes/macrophages. Recent studies have shown that TM is a multi-functional molecule participated in inflammation and cellular adhesion. Abdominal aortic aneurysm (AAA) is a degenerative disease of the abdominal aorta which results in a weakened and systemic dilated aorta that is prone to rupture. AAA has been classified as an inflammatory vascular disease and typically characterized by destruction of extracellular matrix, loss of smooth muscle cells in the media, and accumulation of inflammatory cells in lesions. The most important pathogenesis is transmural infiltration of inflammatory cells, including macrophages, which play a pivotal role through release of a cascade of proinflammatory mediators and proteolytic enzymes. Up to now, the role of monocytic TM in AAA formation remains unclear. In this study, to explore whether the monocytic TM modulates AAA formation, we used myeloid-specific TM-deficient mice (LysMcre/TMflox/flox mice). The results showed that TM-deficient mice had reduced aortic expansion, macrophage infiltration, and levels of proinflammatory mediators in the AAA lesion induced by angiotensin II. To pursue the possible mechanism by which monocytic TM participated in AAA formation, inflammatory macrophages were isolated from peritoneal lavages at 4 days after thioglycollate (TG) injection. We found that TM expression was elevated in TG-induced macrophages compared with non-induced resident peritoneal macrophages, suggesting that increased expression of TM might be associated with maturation of inflammatory macrophages. Moreover, genetic deletion or antibody blockade of TM led to reduced monocytes/macrophages adhesion to endothelial cells. In addition, not only proinflammatory mediators but also matrix metalloproteinase 9 in TG-induced TM-deficient macrophages were significantly decreased. In conclusion, our results demonstrate that monocytic TM may contribute to AAA development via modulation of monocyte/macrophage adhesion and proinflammatory mediator secretion. These findings suggest targeting of TM-mediated pathways in monocytes/macrophages might provide a new therapeutic strategy to antagonize AAA progression.