TLR4/MyD88介导NLRP3炎症小体对自发性高血压大鼠房颤易感性的作用研究

Hypertension is associated with innate immune abnormalities. TLR4/MyD88 and downstream factor NLRP3 are the core regulators of innate immune-related inflammatory response. Structural remodeling due to inflammatory response is an important pathophysiological basis for secondary atrial fibrillation in hypertension. Our previous study showed that NLRP3 expression in hypertensive rats was higher than that in normal blood pressure group. The expression of NLRP3 in peripheral blood of patients with hypertension was higher than that of sinus rhythm group. This suggests that NLRP3 plays an important role in atrial fibrillation or hypertension. We hypothesized that hypertension induced TLR4/MyD88-NLRP3 pathway activation, leading to atrial remodel and induced atrial fibrillation. In this study, we tried to express or inhibit the myocardial TLR4 and NLRP3 in spontaneously hypertensive rats(SHR),and to detect the target protein expression, atrial fibrosis, and susceptibility of atrial fibrillation.TLR4,NLRP3 and TGF-β were inhibited or overexpressed in myocardial fibroblasts, and the role of TLR4/MyD88 mediated NLRP3 inflammasome in hypertension secondary to atrial fibrillation was described, which in order to provide the new targets for reducing the susceptibility to atrial fibrillation in patients with hypertension.

高血压与固有免疫异常活化有关，TLR4/MyD88及其下游因子NLRP3是固有免疫相关炎症反应的核心调控因子，炎症反应所致的结构重构是高血压继发房颤发生的重要病理生理基础。我们前期研究表明，高血压大鼠心肌NLRP3表达高于正常血压组；高血压合并房颤患者外周血NLRP3表达高于窦律组；这提示NLRP3在房颤或高血压中均有重要作用。我们推测：自发性高血压大鼠（SHR）心脏TLR4/MyD88-NLRP3通路异常激活，导致心房纤维化进而诱发房颤。本课题组拟过表达或抑制表达SHR心脏TLR4及NLRP3，检测对目的蛋白、心房纤维化及房颤易感性的影响。在心肌成纤维细胞中分别抑制或过表达TLR4、NLRP3、TGF-β，阐明TLR4/MyD88介导NLRP3炎症小体在高血压继发房颤中的作用，为降低高血压患者房颤易感性提供新的干预靶点。

房颤是最常见的心律失常，高血压是房颤常见的独立危险因素之一。高血压患者存在固有免疫异常激活，介导下游炎症反应发生，与心房纤维化及房颤的发生有关。课题组发现22周龄的自发性高血压大鼠（Spontaneously Hypertensive Rats，SHR）左心房心肌组织TLR4/NLRP3-TGF-β/Smads表达明显上调，证实SHR血压高伴有固有免疫激活。在体内实验中上调TLR4的表达可以激活NLRP3炎症小体，升高TGF-β的表达，促进左心房心肌纤维化，加重左心房结构重构，升高SHR大鼠的房颤易感性。下调TLR4的表达可以抑制NLRP3炎症小体激活，降低TGF-β的表达，抑制左心房心肌纤维化，改善左心房结构重构，降低SHR大鼠的房颤易感性。在体外实验中，转染TLR4-shRNA在心脏成纤维细胞中降低TLR4的表达，可抑制NLRP3炎症小体的激活，降低TGF-β的表达，抑制AngⅡ诱导的心脏成纤维细胞增殖。本研究在不同的层面论证了TLR4调节NLRP3/TGF-β表达在SHR左心房重构，心房颤动易感性的作用。高血压中TLR4/MyD88/NLRP3异常激活可促进心房重构，进而诱发房颤。抑制TLR4可以限制NLRP3炎症小体激活，抑制左心房心肌纤维化，改善左心房结构重构，为降低高血压患者房颤易感性提供新的干预靶点。