Membrane-Bound Thrombomodulin Regulates Macrophage Inflammation in Abdominal Aortic Aneurysm

Kuan Chieh Wang, Yi Heng Li, Guey Yueh Shi, Hung Wen Tsai, Chawn Yau Luo, Min Hua Cheng, Chih Yuan Ma, Yun Yan Hsu, Tsung Lin Cheng, Bi Ing Chang, Chao Han Lai, Hua Lin Wu

研究成果: Article

19 引文 斯高帕斯(Scopus)


Objective-Thrombomodulin (TM), a glycoprotein constitutively expressed in the endothelium, is well known for its anticoagulant and anti-inflammatory properties. Paradoxically, we recently found that monocytic membrane-bound TM (ie, endogenous TM expression in monocytes) triggers lipopolysaccharide-and gram-negative bacteria-induced inflammatory responses. However, the significance of membrane-bound TM in chronic sterile vascular inflammation and the development of abdominal aortic aneurysm (AAA) remains undetermined. Approach and Results-Implicating a potential role for membrane-bound TM in AAA, we found that TM signals were predominantly localized to macrophages and vascular smooth muscle cells in human aneurysm specimens. Characterization of the CaCl2-induced AAA in mice revealed that during aneurysm development, TM expression was mainly localized in infiltrating macrophages and vascular smooth muscle cells. To investigate the function of membrane-bound TM in vivo, transgenic mice with myeloid-(LysMcre/TMflox/flox) and vascular smooth muscle cell-specific (SM22-cretg/TMflox/flox) TM ablation and their respective wild-type controls (TMflox/flox and SM22-cretg/TM+/+) were generated. In the mouse CaCl2-induced AAA model, deficiency of myeloid TM, but not vascular smooth muscle cell TM, inhibited macrophage accumulation, attenuated proinflammatory cytokine and matrix metalloproteinase-9 production, and finally mitigated elastin destruction and aortic dilatation. In vitro TM-deficient monocytes/macrophages, versus TM wild-type counterparts, exhibited attenuation of proinflammatory mediator expression, adhesion to endothelial cells, and generation of reactive oxygen species. Consistently, myeloid TM-deficient hyperlipidemic mice (ApoE-/-/LysMcre/TMflox/flox) were resistant to AAA formation induced by angiotensin II infusion, along with reduced macrophage infiltration, suppressed matrix metalloproteinase activities, and diminished oxidative stress. Conclusions-Membrane-bound TM in macrophages plays an essential role in the development of AAA by enhancing proinflammatory mediator elaboration, macrophage recruitment, and oxidative stress.

頁(從 - 到)2412-2422
期刊Arteriosclerosis, thrombosis, and vascular biology
出版狀態Published - 2015 十一月 1

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

指紋 深入研究「Membrane-Bound Thrombomodulin Regulates Macrophage Inflammation in Abdominal Aortic Aneurysm」主題。共同形成了獨特的指紋。

  • 引用此