From 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.).
Arterioscler Thromb Vasc Biol. 2015 Nov;35(11):2412-22. doi: 10.1161/ATVBAHA.115.305529. Epub 2015 Sep 3.
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.
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.
Membrane-bound TM in macrophages plays an essential role in the development of AAA by enhancing proinflammatory mediator elaboration, macrophage recruitment, and oxidative stress.
血栓调节蛋白（TM）是一种在内皮细胞中持续表达的糖蛋白，以其抗凝和抗炎特性而闻名。矛盾的是，我们最近发现单核细胞膜结合 TM（即在单核细胞中表达的内源性 TM）触发脂多糖和革兰氏阴性菌诱导的炎症反应。然而，膜结合 TM 在慢性无菌性血管炎症和腹主动脉瘤（AAA）发展中的意义仍未确定。
暗示膜结合 TM 在 AAA 中可能具有作用，我们发现 TM 信号主要定位于人动脉瘤标本中的巨噬细胞和血管平滑肌细胞。对小鼠氯化钙诱导的 AAA 的特征分析表明，在动脉瘤形成过程中，TM 表达主要定位于浸润的巨噬细胞和血管平滑肌细胞。为了研究膜结合 TM 在体内的功能，我们生成了骨髓（LysMcre/TM(flox/flox)）和血管平滑肌细胞特异性（SM22-cre(tg)/TM(flox/flox)）TM 缺失的转基因小鼠及其各自的野生型对照（TM(flox/flox)和 SM22-cre(tg)/TM(+/+)）。在小鼠氯化钙诱导的 AAA 模型中，骨髓 TM 缺失而非血管平滑肌细胞 TM 缺失抑制了巨噬细胞的积累，减弱了促炎细胞因子和基质金属蛋白酶-9 的产生，最终减轻了弹性蛋白破坏和主动脉扩张。在体外 TM 缺陷单核细胞/巨噬细胞中，与 TM 野生型相比，促炎介质表达、与内皮细胞的黏附以及活性氧的产生减弱。一致地，骨髓 TM 缺陷高脂血症小鼠（ApoE(-/-)/LysMcre/TM(flox/flox)）对血管紧张素 II 输注诱导的 AAA 形成具有抗性，同时减少了巨噬细胞浸润、抑制了基质金属蛋白酶活性并减轻了氧化应激。
巨噬细胞中的膜结合 TM 通过增强促炎介质的表达、巨噬细胞募集和氧化应激，在 AAA 的发展中起着至关重要的作用。
