Liu Yang, Lv Haichen, Tan Ruopeng, An Xiangbo, Niu Xiao-Hui, Liu Yue-Jian, Yang Xiaolei, Yin Xiaomeng, Xia Yun-Long
From the Institute of Heart and Vascular Diseases (Y.L., R.T., X.A., X.N., X.Y., Y.-L.X.), the First Affiliated Hospital of Dalian Medical University, China.
Department of Cardiology (H.L., X.Y., Y.-L.X.), the First Affiliated Hospital of Dalian Medical University, China.
Hypertension. 2020 Dec;76(6):1856-1867. doi: 10.1161/HYPERTENSIONAHA.120.15016. Epub 2020 Nov 11.
Hypertension is a risk factor of atrial fibrillation (AF), and a certain number of patients with hypertension were found with an enlarged left atrium. Platelet activation is found in patients with hypertension or pressure overload/Ang II (angiotensin II)-induced hypertensive animal models and contribute to ventricular fibrosis. Whether hypertension-induced atrial fibrosis is mediated by platelets remains unknown. Our previous experimental data showed that platelet-derived TGF-β1 (transforming growth factor-β1) was reduced in patients with hypertensive AF. The present study is to investigate whether platelet-derived TGF-β1 promotes Ang II-induced atrial fibrosis and AF. Platelet activation and atrial platelet accumulation were measured in sinus rhythm controls, normotensive AF, and patients with hypertensive AF. Ang II (1500 ng/kg per minute, 3 weeks) infused mice with pharmacological (clopidogrel) and genetic platelet inhibition (TGF-β1 deletion in platelets) were used. Platelet activation, atrial structural remodeling, atrial electrical transmission, AF inducibility, inflammation, and fibrosis were measured in mice. We found that circulating platelets were activated in patients with hypertensive AF. A large amount of platelet was accumulated in the atriums of patients with hypertensive AF. Both clopidogrel treatment and platelet-specific deletion of TGF-β1 attenuated Ang II-induced structural remodeling, atrial electrical transmission, AF inducibility, as well as atrial inflammation and fibrosis than mice without interventions. Furthermore, clopidogrel blocked atrial platelet accumulation and platelet-fibroblast conjugation. Platelets promoted atrial fibroblast differentiation in cell culture. Profibrotic actions of platelets are largely via activation of atrial fibroblasts by releasing TGF-β1 and inducing platelet-fibroblast conjugation, and platelet inhibition is sufficient to inhibit atrial fibrosis and AF inducibility.
高血压是心房颤动（AF）的一个危险因素，并且发现一定数量的高血压患者左心房增大。在高血压患者或压力超负荷/血管紧张素II（Ang II）诱导的高血压动物模型中发现血小板活化，并导致心室纤维化。高血压诱导的心房纤维化是否由血小板介导尚不清楚。我们之前的实验数据表明，高血压性AF患者血小板衍生的转化生长因子-β1（TGF-β1）减少。本研究旨在探讨血小板衍生的TGF-β1是否促进Ang II诱导的心房纤维化和AF。在窦性心律对照组、血压正常的AF患者和高血压性AF患者中测量血小板活化和心房血小板聚集情况。使用经药理学（氯吡格雷）和基因血小板抑制（血小板中TGF-β1缺失）的小鼠，以每分钟1500 ng/kg的剂量输注Ang II，持续3周。在小鼠中测量血小板活化、心房结构重塑、心房电传导、AF诱导性、炎症和纤维化情况。我们发现高血压性AF患者的循环血小板被激活。大量血小板积聚在高血压性AF患者的心房中。与未干预的小鼠相比，氯吡格雷治疗和血小板特异性缺失TGF-β1均减轻了Ang II诱导的结构重塑、心房电传导、AF诱导性以及心房炎症和纤维化。此外，氯吡格雷阻止了心房血小板积聚和血小板-成纤维细胞结合。在细胞培养中，血小板促进心房成纤维细胞分化。血小板的促纤维化作用主要是通过释放TGF-β1激活心房成纤维细胞并诱导血小板-成纤维细胞结合，而抑制血小板足以抑制心房纤维化和AF诱导性。
