CXCR6在压力超负荷诱导心室重构中的作用及机制研究

The proinflammatory cytokines such as Angiotensin II and C- reactive protein are increased during hypertension, which further promote the progress of pressure overload-induced ventricular remodeling and heart failure.However, the underlying molecular mechanism is poorly understood. Our previous study showed that CXCR6 receptor played an important role in inducing the infiltration of inflammatory cells in myocardium during ischemia/reperfusion (I/R) injury. CXCR6 knockout significantly improved I/R-induced myocardial injury and ventricular remodeling. The recent study also reported that shear stress stimulated CXCR6 receptor and the later mediated arterial thrombosis and vascular remodeling, which indicated a possible role of CXCR6 in pressure overload-induced cardiac remodeling. In addition, we revealed that pressure overload-induced ventricular remodeling was dependent on the activation of TGF-β signaling pathway. Based on these results, we aim to investigate the potential mechanism of pressure overload-induced ventricular remodeling in CXCR6-/- mice with a TAC model. The present study stresses on the effects and relations of CXCR6 on vascular injury and myocardial remodeling, and CXCR6-mediated paracrine effect of inflammatory cytokines on TGF-β downstream signaling. To illustrate the protective role of CXCR6 deficiency in improving pressure overload-induced ventricular remodeling. The current experiment may shed light on the novel target for the fundamental study and clinical therapy of myocardial remodeling.

持续性高血压可诱导血管紧张素II、C-反应蛋白等促炎因子的分泌，炎症反应进一步加重了压力超负荷下的心室重构和心力衰竭，其潜在的病理分子机制尚不明确。我们前期研究发现，CXCR6受体在趋化心脏炎症细胞浸润的过程中发挥重要作用，缺血-再灌注导致心肌损伤和心室重构在CXCR6基因敲除小鼠明显减轻。国外最新报道CXCR6在剪切应力下可致动脉血栓和血管重构，提示CXCR6可能是研究压力超负荷诱导心室重构的重要靶点。此外，我们还发现TGF-β信号通路的激活促进压力超负荷下心肌重塑的过程。据此，本项目拟从研究CXCR6受体出发，构建CXCR6敲除小鼠的压力超负荷（TAC）模型，探讨CXCR6在血管损伤与心肌重塑中的作用和联系，重点阐明CXCR6介导炎症因子的旁分泌效应和对TGF-β下游信号调控的分子机制，明确CXCR6敲除对于改善压力超负荷引起心室重构的保护作用，为预防和治疗结构性心脏病寻找合适的靶点。

近年来炎症激活在心脏重构中的重要作用正不断被引起重视，而炎症在压力超负荷诱导的心脏重构中的研究研究报道甚少，分子机制也不十分明确。我们通过这项研究，基本阐明了CXCR6受体是介导炎症免疫细胞向心脏浸润，释放炎症因子，并激活凋亡相关受体，促进心肌细胞凋亡和胶原沉积，加剧压力超负荷下左心室发生重构的重要诱因之一。在研究过程中，我们有了一些阶段性的发现和结论：（1）CXCR6受体并不是如我们设想的通过TGF-β信号通路促进下游smad3蛋白活化，进而导致压力超负荷下的心肌纤维化；而是通过非经典的凋亡相关受体途径——TNF-α一型受体（TNFRI）促进了心脏重构效应。（2）TNFRI的激活除了加速MMP9的水解活化之外，还通过交联激活AngII受体一型受体（AT1R）并促使NOX4蛋白的表达增加，造成心肌氧化应激损伤的增加。（3）CXCR6受体可诱导一类iNKT细胞的成熟和向心肌局部浸润，通过释放大量IL-17a因子引起心肌的损伤和重构。IL-17a基因敲除小鼠正在构建过程中，此项研究还将继续深入IL-17a是否参与了CXCR6诱导心脏重构过程中发挥的重要作用和相关病理分子机制。截止目前，我们课题组已经发表受本项目资助SCI论文4篇，培养博士研究生2名。