CXCR7/p38MAPK/PGC-1α信号通路调控线粒体功能加快细胞修复高血压血管损伤的研究

Hypertension-induced vascular endothelial injury leads to the initiation and development of cardiovascular diseases. Endothelial progenitor cells (EPCs) derived from bone marrow play a critical role in maintaining the integrity of vascular endothelium after arterial injury. Decline in number and function of early EPCs is responsible for the loss of normal endothelial homeostasis in hypertension. Therefore, restoration of EPC-mediated endothelial reparative capacity in patients with hypertension may be an important strategy for the optimal treatment of hypertension aimed at reducing the high incidence of hypertension-related cardiovascular diseases. Mitochondria is the important link between cardiovascular risk factors and endothelial injury, and its function is related to cell function and apoptosis. Our previous research suggested that EPCs from hypertensive patients exert mitochondrial abnormal and dysfunction compared with healthy subject. However, the effects and underlying mechanisms of mitochondrial dysfunction to the pathophysiology of EPCs-related vascular endothelium injury in hypertension remain unknown. The study will construct the experimental model of cell culture in vitro, animal carotid artery injured model and clinical experiment, to investigate the mitochondrial function and their relation to endothelial repair capacity of EPCs in hypertensive patients and normal subjects, and to explore the improvement of endothelial repair capacity related to CXCR7/p38MAPK/PGC-1α signaling, which result in increased mitochondrial function and cell function of EPCs from hypertensive patients. The study will demonstrate that mitochondrial dysfunction leads to the loss of EPC-related endothelial repair capacity in hypertensive patients, and provides new biomarkers and vital theoretical basis for early warning and effective intervention of hypertensive vascular injury.

高血压导致血管内皮损伤是动脉粥样硬化血管疾病发生发展的关键。血管内皮完整与内皮祖细胞功能密切相关，深入研究提高内皮祖细胞血管修复能力的方法及分子机制是防治高血压血管疾病的有效策略。线粒体是连接心血管危险因素与内皮损伤的重要环节，细胞功能、数量下降均与线粒体功能障碍有关。我们预实验发现高血压内皮祖细胞存在线粒体功能障碍，能否通过改善线粒体功能障碍上调细胞功能活性和减少凋亡从而提高血管修复能力及具体分子机制尚有待于进一步研究。本课题拟从细胞、动物和临床水平，探讨高血压内皮祖细胞线粒体功能障碍与血管修复能力下降的关系；研究调控CXCR7/p38MAPK/PGC-1α信号通路改善线粒体功能障碍加快内皮修复的作用。本课题从线粒体角度，阐明高血压内皮祖细胞功能下降与线粒体功能障碍的关系，揭示调控内皮祖细胞线粒体功能从而保护血管的新机制，为高血压血管损伤早期预警和有效干预提供新的靶点和和重要理论依据。

高血压导致血管内皮损伤是动脉粥样硬化血管疾病发生发展的关键。高血压内皮祖细胞血管损伤修复能力下降，深入研究提高内皮祖细胞功能的方法及分子机制是防治高血压血管疾病的有效策略。线粒体功能与细胞功能密切相关。高血压内皮祖细胞是否存在线粒体功能障碍及能否通过改善线粒体功能障碍上调细胞功能活性从而提高血管修复能力及具体分子机制尚有待于进一步研究。本课题从细胞、动物和临床水平，探讨高血压内皮祖细胞线粒体功能障碍与血管修复能力下降的关系；研究调控CXCR7信号通路改善线粒体功能障碍加快内皮修复的作用。首先，通过研究高血压内皮祖细胞线粒体功能障碍与细胞功能活性的关系，发现高血压患者内皮祖细胞线粒体膜电位下降、ROS水平升高、mtDNA损伤增加且线粒体结构异常，揭示高血压内皮祖细胞的确存在线粒体功能障碍。同时高血压内皮祖细胞功能下降以及在体再内皮化能力减弱，研究发现通过改善线粒体功能可上调内皮祖细胞的血管损伤修复能力。其次，高血压疾病状态下内皮祖细胞CXCR7通路下调是血管损伤重要分子生物学机制，研究证实CXCR7信号通路对调节高血压内皮祖细胞线粒体功能具有重要作用，利用腺病毒转染上调CXCR7水平后可改善线粒体损伤并改善再内皮化能力。研究发现CXCR7/SIRT3/SOD2信号通路是调控线粒体功能从而影响高血压血管修复能力的重要分子机制；发现CXCR7/p38MAPK信号通路对高血压内皮祖细胞功能的调控作用， PGC-1α及PINK1是CXCR7调控高血压内皮祖细胞功能的重要分子靶点。再次，探讨了内皮祖细胞可通过CXCR7/p-ERK信号通路调控血管新生能力，揭示CXCR7信号通路保护血管的新机制。此外，研究还发现黄连素可通过调控CXCR4信号通路改善高血压前期内皮祖细胞血管修复能力，为高血压病早期防治及药物开发提供新靶点。因此，本课题从线粒体角度阐明高血压EPC功能下降与线粒体功能障碍的关系，提出高血压血管损伤修复的新机制，揭示改善内皮祖细胞功能从而保护血管的新靶点，为高血压血管损伤性早期预警和有效干预提供新的思路和重要的理论依据。

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