Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China; Department of Cardiology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou 213003, Jiangsu Province, China.
Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China.
Biochem Biophys Res Commun. 2018 Jun 7;500(3):550-556. doi: 10.1016/j.bbrc.2018.04.071. Epub 2018 Apr 24.
It was previously found that patients with symptom of myocardial dysfunction had increased levels of thrombin. Apixaban is one of the novel oral anticoagulant drugs widely used in clinic. As the inhibitor of FXa (prothrombin), it inhibits prothrombin conversion into thrombin leading to thrombin deficiency in vivo. However, the effects of apixaban on myocardial fibrosis were still unclear, and the concomitant molecular mechanisms remain to be investigated. Here, we showed that myocardial fibrosis-bearing mice induced by continuous myocardial ischemia (MI) had higher levels of thrombin. Orally administration of apixaban significantly abrogated fibrosis condition and thrombin levels. In vitro, thrombin induced collagen deposition in primary cardiac fibroblasts in a dose-dependent manner. Mechanistic experiments showed that thrombin induced collagen deposition by activation of the Par-1-coupled Gq/PKC signaling. Genetic ablation of Gq or pharmacological inhibition of PKC effectively blunted thrombin-induced collagen deposition in cardiac fibroblasts. Moreover, administration of PKC inhibitor or Gq antagonist obviously blocked MI-induced myocardial fibrosis in mice. To conclude, apixaban attenuates MI-induced myocardial fibrosis by inhibition of thrombin-dependent Par-1/Gq/PKC signaling axis.
先前发现，有心肌功能障碍症状的患者凝血酶水平升高。阿哌沙班是一种广泛应用于临床的新型口服抗凝药物。作为 FXa（凝血酶原）的抑制剂，它抑制凝血酶原转化为凝血酶，导致体内凝血酶缺乏。然而，阿哌沙班对心肌纤维化的影响尚不清楚，其伴随的分子机制仍有待研究。在这里，我们发现，由持续心肌缺血（MI）诱导的心肌纤维化小鼠的凝血酶水平更高。阿哌沙班口服给药可显著减轻纤维化程度和凝血酶水平。在体外，凝血酶以剂量依赖的方式诱导原代心肌成纤维细胞胶原沉积。机制实验表明，凝血酶通过激活 PAR-1 偶联的 Gq/ PKC 信号通路诱导胶原沉积。Gq 的基因敲除或 PKC 的药理学抑制可有效减弱心肌成纤维细胞中凝血酶诱导的胶原沉积。此外，PKC 抑制剂或 Gq 拮抗剂的给药可明显阻断 MI 诱导的小鼠心肌纤维化。总之，阿哌沙班通过抑制凝血酶依赖性 PAR-1/Gq/PKC 信号轴来减轻 MI 诱导的心肌纤维化。
