Boyd John H, Chau Edmond H, Tokunanga Chiho, Bateman Ryon M, Haljan Greg, Davani Ehsan Y, Wang Yinjin, Walley Keith R
University of British Columbia Critical Care Research Laboratories, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
Crit Care. 2008;12(1):R2. doi: 10.1186/cc6213. Epub 2008 Jan 3.
Cardiomyocytes exposed to inflammatory processes express intracellular adhesion molecule-1 (ICAM-1). We investigated whether fibrinogen and fibrinogen degradation products, including D-dimer, could alter cardiomyocyte contractile function through interaction with ICAM-1 found on inflamed cardiomyocytes.
In vivo, rats were injected with endotoxin to model systemic inflammation, whereas isolated rat cardiomyocytes were treated with tumor necrosis factor-alpha to model the inflammatory environment seen following exposure to bacterial products such as lipopolysaccharide.
In vivo, endotoxin administration profoundly decreased cardiac contractile function associated with a large increase in intracardiac ICAM-1 and perivascular fibrinogen. Confocal microscopy with double-staining of isolated rat cardiomyocytes demonstrated colocalization of ICAM-1 and fibrinogen. This interaction was disrupted through pre-treatment of the cells with an ICAM-1-blocking antibody. Functionally, isolated rat cardiomyocyte preparations exhibited decreased fractional shortening when incubated with fibrinogen, and through the use of synthetic peptides, we determined that residues 117-133 of the fibrinogen gamma chain are responsible for this interaction with ICAM-1. Despite having crosslinked gamma chains, D-dimer retained the ability to decrease cardiomyocyte contractility.
Site 117-133 of the fibrinogen gamma chain is able to depress cardiomyocyte contractility through binding ICAM-1.
暴露于炎症过程的心肌细胞会表达细胞间黏附分子-1（ICAM-1）。我们研究了纤维蛋白原和包括D-二聚体在内的纤维蛋白原降解产物是否能通过与炎症心肌细胞上发现的ICAM-1相互作用来改变心肌细胞的收缩功能。
在体内，给大鼠注射内毒素以模拟全身炎症，而分离的大鼠心肌细胞则用肿瘤坏死因子-α处理，以模拟暴露于脂多糖等细菌产物后出现的炎症环境。
在体内，给予内毒素会显著降低心脏收缩功能，同时心脏内ICAM-1和血管周围纤维蛋白原大幅增加。对分离的大鼠心肌细胞进行双重染色的共聚焦显微镜检查显示ICAM-1和纤维蛋白原共定位。通过用ICAM-1阻断抗体对细胞进行预处理，这种相互作用被破坏。在功能上，分离的大鼠心肌细胞制剂在与纤维蛋白原孵育时表现出缩短分数降低，并且通过使用合成肽，我们确定纤维蛋白原γ链的117-133位残基负责与ICAM-1的这种相互作用。尽管具有交联的γ链，D-二聚体仍保留降低心肌细胞收缩力的能力。
纤维蛋白原γ链的117-133位能够通过结合ICAM-1来降低心肌细胞的收缩力。
