Katoh Shigehiko, Honda Shintaro, Watanabe Tetsu, Suzuki Satoshi, Ishino Mitsunori, Kitahara Tatsuro, Funayama Akira, Netsu Shunsuke, Sasaki Toshiki, Shishido Tetsuro, Miyamoto Takuya, Sadahiro Mitsuaki, Kubota Isao
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.
Heart Vessels. 2014 Mar;29(2):263-72. doi: 10.1007/s00380-013-0369-3. Epub 2013 Jun 11.
Low-grade inflammation associated with heart failure (HF) is known to deteriorate cardioembolic stroke in patients with atrial fibrillation (AF). Little is known about the relationship between atrial endothelial impairment induced by innate immunity and thrombus formation. We examined whether atrial endothelial impairment through Toll-like receptor (TLR) 4 signaling causes atrial thrombogenesis. TLR4, heat shock protein 60, and vascular cell adhesion molecule (VCAM)-1 expression were higher in the atrium of AF patients who underwent valve replacement surgery with HF compared with those without it (p < 0.05). We created thoracic transverse aortic constriction (TAC) in TLR4 knock-out (KO) and wild-type (WT) mice. Atrial thrombosis was observed less frequently in TLR4 KO mice (4/15) than in WT mice (16/20) 4 weeks after TAC despite similar severity of heart failure. The decrease in endothelial nitric oxide synthase (eNOS) phosphorylation and increase in VCAM-1 and plasminogen activator inhibitor (PAI)-1 expression, observed in the atrium of WT mice following TAC, were significantly attenuated in TLR4 KO mice (p < 0.05). Nuclear factor-κB (NF-κB) activation after TAC was attenuated in TLR4 KO mice compared with WT mice. Activation of mitogen-activated protein kinase p38 (p38) after TAC was also attenuated in TLR4 KO mice (p < 0.05). Thus, increased VCAM-1 and PAI-1, and decreased eNOS phosphorylation through the TLR4/NFκB/p38 pathway, may be associated with atrial thrombogenesis in the heart failure mice model. Atrial endothelial impairment through the TLR4 signaling may play a role in atrial thrombogenesis in AF patients with HF.
已知与心力衰竭（HF）相关的低度炎症会使心房颤动（AF）患者的心脏栓塞性中风恶化。关于先天免疫诱导的心房内皮损伤与血栓形成之间的关系，人们知之甚少。我们研究了通过Toll样受体（TLR）4信号传导引起的心房内皮损伤是否会导致心房血栓形成。与未合并HF而接受瓣膜置换手术的AF患者相比，合并HF接受瓣膜置换手术的AF患者心房中TLR4、热休克蛋白60和血管细胞黏附分子（VCAM）-1的表达更高（p<0.05）。我们在TLR4基因敲除（KO）小鼠和野生型（WT）小鼠中制造了胸段横向主动脉缩窄（TAC）。尽管心力衰竭的严重程度相似，但在TAC术后4周，TLR4 KO小鼠（4/15）的心房血栓形成发生率低于WT小鼠（16/20）。TAC术后WT小鼠心房中观察到的内皮型一氧化氮合酶（eNOS）磷酸化减少以及VCAM-1和纤溶酶原激活物抑制剂（PAI）-1表达增加，在TLR4 KO小鼠中显著减弱（p<0.05）。与WT小鼠相比，TLR4 KO小鼠TAC术后核因子-κB（NF-κB）激活减弱。TAC术后丝裂原活化蛋白激酶p38（p38）的激活在TLR4 KO小鼠中也减弱（p<0.05）。因此，通过TLR4/NFκB/p38途径导致的VCAM-1和PAI-1增加以及eNOS磷酸化减少，可能与心力衰竭小鼠模型中的心房血栓形成有关。通过TLR4信号传导引起的心房内皮损伤可能在合并HF的AF患者的心房血栓形成中起作用。
