The role of monocytic thrombomodulin in abdominal aortic aneurysm formation

Abstract

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-speci?c TM-de?cient mice (LysMcre/TMflox/flox mice) The results showed that TM-de?cient 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

Date of Award	2014 Jul 30
Original language	English
Supervisor	Hua-Lin Wu (Supervisor)