易卒中自发性高血压大鼠血脑屏障损害中ABCB1（P-糖蛋白）作用机制的研究

ABCB1 (P-glycoprotein) is the first ABC protein related to multidrug resistance (MDR). In the last few years, increasing evidence has pointed to an involvement of ABCB1 via the mineralocorticoid receptor (MR) with target organ damage in essential hypertension. The mechanism of the effect of ABCB1 on cerebrovascular injury in hypertension has not been defined previously. In this study, using a stroke-prone hypertensive model, we will examine essential hypertension-induced BBB impairment. Using Laser capture microdissection (LCM) to identify endothelial cells (ECs), we will examine gene expressions of ABCB1 in the BBB-damaged hippocampal ECs of SHRSP and in ECs of Wistar Kyoto (WKY) rats as controls. The fluorescent signals of ABCB1 in hippocampal vessels will be viewed under a confocal microscope. At the same time, we will study the protective effect of MR antagonist on BBB impairment in SHRSP and the effect on expressions of ABCB1. To further clarify roles of ABCB1 in BBB-damaged ECs, using cultured rat brain microvascular endothelial cells (RBMVEC), we will determine whether the expression of ABCB1 are modulated by aldosterone-induced ROS production through activation of NADPH Oxidase in RBMVEC. The results of the study will suggest that ABCB1 is an important protein related to essential hypertension-induced BBB impairment. Aldosterone-induced ROS production may play a role in the pathogenesis of BBB impairment and upregulated expression of ABCB1 in hypertension.

近年研究表明ABC转运蛋白ABCB1（P-糖蛋白）通过盐皮质激素受体（MR）参与高血压引起的靶器官损害，而ABCB1在高血压引起的中枢神经系统功能障碍的作用机制尚不明确。我们的前期研究发现ABCB1在高血压引起的血脑屏障损害中表达增高，本项目拟以易卒中自发性高血压大鼠（SHRSP）为动物模型，利用激光捕获显微切割技术（Laser capture microdissection，LCM）直接检测血脑屏障微血管内皮细胞ABCB1的基因表达，并且研究MR拮抗剂对SHRSP大鼠血脑屏障损害的保护作用及ABCB1表达的影响。在此基础上，体外细胞培养研究醛固酮刺激大鼠脑微血管内皮细胞活性氧物质产生及ABCB1表达之间的相关性。本研究旨在证明ABCB1是原发性高血压血脑屏障损害的重要相关蛋白，醛固酮诱导活性氧物质产生是原发性高血压血脑屏障损害及脑微血管内皮细胞ABCB1表达增高的作用机制之一。

近年研究表明ABC转运蛋白ABCB1（P-糖蛋白）通过盐皮质激素受体（MR）参与高血压引起的靶器官损害，而ABCB1在高血压引起的中枢神经系统功能障碍的作用机制尚不明确。我们的前期研究发现ABCB1在高血压引起的血脑屏障损害中表达增高，本项目以易卒中自发性高血压大鼠（SHRSP）为动物模型，利用激光捕获显微切割技术（Laser capture microdissection，LCM）直接检测血脑屏障微血管内皮细胞ABCB1的基因表达，并且研究MR拮抗剂对SHRSP大鼠血脑屏障微血管内皮细胞ABCB1表达的影响。在此基础上，体外细胞培养研究醛固酮刺激大鼠脑微血管内皮细胞活性氧物质产生及ABCB1表达之间的相关性。本研究证明ABCB1是原发性高血压血脑屏障损害的重要相关蛋白，醛固酮诱导活性氧物质产生是原发性高血压血脑屏障损害及脑微血管内皮细胞ABCB1表达增高的作用机制之一。