氧化应激激活CCECs中Hippo-YAP信号通路在糖尿病ED发病机制中的作用研究

Erectile dysfunction (ED) is one of the serious complications of patients with diabetes mellitus, which has had been seriously affected male life quality, the process is accompanied by oxidative stress, which leads to dysfunction of corpus cavernosum endothelial cells(CCECs), however, the mechanism remains unclear. In our precious study, we had established rat models with type 2 diabetic erectile dysfunction（DED）, which successfully simulated the oxidative stress in vivo, and we found that the expression of YAP, the key downstream molecules of Hippo signaling pathway, and F-actin, one of the cytoskeletal proteins, were both significantly up-regulated in the damaged CCECs, and they had great positive correlation and negative correlation with the NOS protein, which suggested us it might play an important role in the development of diabetic erectile dysfunction. Therefore, we speculate that the abnormalities of Hippo-YAP signaling pathway and cytoskeleton may lead to morphological change of tissue organ. Based on the scientific hypothesis, this program aims to investigate the relationship between change of Hippo signaling pathway and the interaction of cytoskeletal proteins, trying to find out the key factors and potential regulatory factors, and to illuminate the action mechanism through cell experiments of oxidative stress in vitro and rat models with type 2 diabetic erectile dysfunction. On the basis, we may take effective measures to reduce the damage of CCECs effectively, which has important scientific significance to improve the prognosis of DED patients.

勃起功能障碍(ED)是男性糖尿病患者的严重并发症之一，极大影响着男性生活质量，此过程伴随氧化应激并导致阴茎海绵体内皮细胞（CCECs）损伤，但具体机制报道较少。我们前期研究发现：在大鼠2型糖尿病ED（DED）模型及模拟氧化应激的细胞实验中，Hippo-YAP信号通路关键分子YAP与细胞骨架蛋白F-actin在损伤的CCECs中表达均明显上调且呈正相关关系，而与ED密切相关的NOS蛋白负相关；提示我们其影响CCECs的功能并在DED中发挥重要作用。因此，我们推测在氧化应激损伤中，Hippo-YAP信号通路与细胞骨架异常进而导致组织器官功能改变。本项目拟针对该科学假说，通过氧化应激的细胞实验和2型糖尿病ED大鼠模型，研究DED 中Hippo-YAP信号通路的改变与细胞骨架之间的作用，并阐明调控的具体机制。在此基础上加以有效干预可有效减轻CCECs的损伤，对改善DED患者预后有着重要的科学意义。

勃起功能障碍(ED)是男性糖尿病患者的严重并发症之一，极大影响着男性生活质量，我们通过iTRAQ联合LC-MS/MS分析鉴定，通过Genecards、KEGG、Pubmed数据库进行生物信息学分析发现上调的差异基因中PROL1和下调的差异基因中SPTA1 (Spectrin Alpha, Erythrocytic 1，血影蛋白α，红细胞1)与生殖系统、勃起功能密切相关，这些分子将可能为ED 的早期预警、早期诊断、早期治疗及预后的监测提供一些潜在的预警分子或干预靶点；通过建立的成熟的阴茎海绵体内皮细胞氧化应激损伤及HUVECs氧化应激损伤模型，研究发现：HMOX1在HX诱导内皮细胞氧化应激中发挥重要作用、HFD可能通过激活PI3K/AKT，上调NF-κB、TNF-α和IL-6等的表达水平，促进大鼠勃起功能障碍的发生；高脂饮食大鼠阴茎海绵体组织中SPTA1的阳性表达下降、SPTA1的下调激活Hippo信号通路诱导CCSMCs发生焦亡、表型发生变化；最重要的是，我们首次证实Hippo-YAP信号通路在糖尿病ED的氧化应激损伤过程中发挥重要作用，这为减轻CCECs的损伤从而改善糖尿病ED提供了有效干预靶点，进而为改善DED患者预后提供了理论基础和可行性。