CFTR氯离子通道：介导原发性饮食性高血压脑血管重构的新靶点

Cystic fibrosis transmembrane conductance regulator (CFTR), a selective ATP-gated chloride channel, is widely expressed in a variety of tissues and cells. Our previous study showed that CFTR knockout affected basal blood pressure and CFTR mediated the development of hypertension induced by high fructose and medium high salt. However, the role of CFTR in cerebrovascular remodeling during hypertension remains unclear. It is established that the imbalance of proliferation and apoptosis of vascular smooth muscle cells (VSMCs)is a key mediator for cerebrovascular remodeling during hypertension. CFTR could regulate cell proliferation and apoptosis. The activity and expression of CFTR are regulated by with-no-lysine kinase 1 (WNK1) and WNK4. In this study, CFTR knockout mice were used to explore the role of CFTR in cerebrovascular remodeling during essential dietary hypertension. The vascular remodeling was evaluated by pressure myography and the cerebral arterial blood flow was measured by laser scanning doppler flowmeter. The CFTR-regulated proliferation and apoptosis of VSMCs were performed to reveal their roles in cerebrovascular remodeling during hypertension. The WNK1/ WNK4-CFTR pathway was investigated through upregulating and downregulating WNK1 and WNK4 expressions in cerebrovascular remodeling during hypertension. Our study will provide new insight into the mechanisms for essential dietary hypertensive cerebrovascular remodeling.

囊性纤维化跨膜转运调节体（CFTR）是ATP门控的选择性氯离子通道，广泛表达于各种组织细胞。我们前期研究证实：CFTR敲除影响基线血压水平，CFTR介导高果糖联合中等高盐诱导的高血压发生发展。然而，CFTR在高血压脑血管重构中的作用尚不清楚。目前认为血管平滑肌细胞增殖凋亡失衡是介导高血压脑血管重构的主要环节。CFTR调控细胞增殖和凋亡，CFTR活性及表达受缺少赖氨酸的丝氨酸/苏氨酸蛋白激酶WNK1和WNK4调控。本研究使用CFTR基因敲除小鼠探索CFTR在原发性饮食性高血压脑血管重构中的作用，采用压力肌动描记术评估血管重构、激光扫描多普勒血流仪测量脑动脉血流；通过细胞增殖凋亡分析揭示CFTR调控的增殖凋亡在高血压脑血管重构中的介导作用；通过上调和下调WNK1和WNK4表达研究WNK1/WNK4-CFTR通路在高血压脑血管重构中的角色，为原发性饮食性高血压脑血管重构发病机制提供新思路。

囊性纤维化跨膜转运调节体（CFTR）是ATP门控的选择性氯离子通道，广泛表达于各种组织细胞。我们前期研究证实：CFTR敲除影响基线血压水平，CFTR介导高果糖联合中等高盐诱导的高血压发生发展。然而，CFTR在高血压脑血管重构中的作用尚不清楚。目前认为血管平滑肌细胞增殖凋亡失衡是介导高血压脑血管重构的主要环节。CFTR调控细胞增殖和凋亡，CFTR活性及表达受缺少赖氨酸的丝氨酸/苏氨酸蛋白激酶WNK1和WNK4调控。本研究使用CFTR基因敲除小鼠探索CFTR在原发性饮食性高血压脑血管重构中的作用，采用压力肌动描记术评估血管重构、激光扫描多普勒血流仪测量脑动脉血流；通过细胞增殖凋亡分析揭示CFTR调控的增殖凋亡在高血压脑血管重构中的介导作用；通过上调和下调WNK1和WNK4表达研究WNK1/WNK4-CFTR通路在高血压脑血管重构中的角色，为原发性饮食性高血压脑血管重构发病机制提供新思路。我们研究发现：实验组颅内段颈内动脉MMP-12、TGF-β蛋白表达明显高于对照组；实验组颅内段颈内动脉Drp1、MiD49蛋白表达明显高于对照组；实验组WNK1和WNK4的表达显著降低；与对照组相比，实验组CFTR降低了约90%。研究结果表明：CFTR在高血压脑血管重构中发挥重要作用。