LOX-1介导内皮祖细胞功能损伤在高血压发生发展中的作用及机制研究

The structural and functional integrity of endothelium plays a pivotal role in the cardiovascular system. Both endothelium cells and the recruitment of endothelial progenitor cells (EPCs) contributed to the integrity of endothelium. The functions of EPCs were impaired in patients and experimental models of hypertension, suggesting that the dysfunction of EPCs are closely associated with hypertension，but the pathophysiological mechanism of EPCs dysfunctions remains unknown. Lectin-like oxidized low-density lipoprotein receptor-1(LOX-1) restrained the proliferation and migration of vascular endothelial cell; Our pilot study showed that the expression of LOX-1 mRNA and protein was up-regulated in EPCs derived from SHR peripheral blood. Based on the above, we hypothesize that increased LOX-1 may mediate the dysfunction of EPCs in hypertension. We will be planning to explore the relationship between EPCs dysfunction and increased LOX-1 in patients, experimental hypertension rats and EPCs. Furthermore, we will investigate the underlying mechanisms responsible for the up-regulation of LOX-1 in EPCs from the hypertension rats and the downstream signaling that LOX-1 promotes EPCs dysfunction. Since clinical studies supported that EPCs function was associated negatively with risk factors of coronary heart diseases, such as hypertension, diabetes, prompting the therapeutic potential of EPCs. This study will contribute to providing new strategies to therapy of hypertension and other cardiovascular system diseases.

血管内皮对维护心血管系统健康有重要意义，血管内皮完整性的维持不仅依赖于内皮细胞，而且与内皮祖细胞（EPCs）的募集有关。高血压动物和患者的EPCs均出现功能失常。但高血压时EPCs功能失常的病理生理机制至今尚不明确。植物凝集素样氧化性低密度脂蛋白受体-1（LOX-1）能够抑制血管内皮细胞的增殖和迁移，我们发现自发性高血压大鼠EPCs的LOX-1表达明显增加。基于此，我们推测：高血压时EPCs的LOX-1表达增加导致细胞功能失常。本项目拟通过临床研究、基因敲除动物和细胞实验，确定高血压时EPCs功能失常与LOX-1表达增加的关系；研究高血压时EPCs LOX-1表达增加的机制和LOX-1表达增加导致EPCs功能损伤的机制。临床研究证实，EPCs功能与高血压、糖尿病等冠心病危险因素呈负相关，EPC 可作为治疗心血管疾病的新靶点。所以本项目有可能为高血压等心血管系统疾病的治疗开辟新的思路。