Membrane-Bound Thrombomodulin Regulates Macrophage Inflammation in Abdominal Aortic Aneurysm
Kuan-Chieh Wang1, Yi-Heng Li1, Guey-Yueh Shi1
1From the Department of Biochemistry and Molecular Biology (K.-C.W., G.-Y.S., M.-H.C., C.-Y.M., Y.-Y.H., B.-I.C., H.-L.W.), Institute of Basic Medical Sciences (K.-C.W.), Cardiovascular Research Center (K.-C.W., Y.-H.L., G.-Y.S., C.-Y.L., C.-Y.M., Y.-Y.H., B.-I.C., C.-H.L., H.-L.W.), Department of Internal Medicine (Y.-H.L.), Department of Pathology (H.-W.T.), and Department of Surgery (C.-Y.L., C.-H.L.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (T.-L.C.).
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/TM(flox/flox)) and vascular smooth muscle cell-specific (SM22-cre(tg)/TM(flox/flox)) TM ablation and their respective wild-type controls (TM(flox/flox) and SM22-cre(tg)/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/TM(flox/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.
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