花青素通过调控p53/miR-200c拮抗氟致内皮细胞损伤的机制研究

Endemic fluorosis is one of the most important endemic diseases in China. Excessive fluoride exposure can cause endothelial cells injury and lead to the initiation and development of cardiovascular diseases, but its mechanism is still unclear. Fluoride-induced endothelial cells injury is mainly manifested by morphological changes of endothelial cells and abnormal expression of endothelial function-related molecules such as NOS; miR-200c, which is closely related to endothelial function, can post-transcriptional regulate the expression of NOS. Combined with our previous results, miR-200c is significantly high expressed in serum of fluorosis patients, we suggested that miR-200c plays an important role in the process of fluoride-induced endothelial cell injury. Previous studies have shown that fluorosis is closely related to oxidative stress, and oxidative stress-sensitive protein p53 can induce high expression of miR-200c. Combining with previous studies, we proposed the following hypothesis: excessive fluoride causes the increase of ROS level in endothelial cells, abnormal content and activity of oxidative or antioxidant enzymes induce high expression of p53 to upregulate miR-200c, which leads to the abnormal expression of target gene NOS, and further induce endothelial cell dysfunction. Anthocyanin is a natural antioxidant with cardiovascular protection and antioxidant effects. It is speculated that anthocyanin may have protective effect on fluorosis and play its role by antagonizing the high expression of p53/miR-200c induced by fluoride.

地方性氟中毒是我国重点防治的地方病之一，过量氟暴露可引起内皮细胞损伤导致心血管疾病的发生发展，但其机制尚不明确。氟致内皮细胞损伤以内皮细胞形态改变，NOS等内皮功能相关分子异常表达为主要表现；miR-200c可转录后调控NOS表达，且与内皮功能密切相关，结合前期实验结果：miR-200c在氟中毒患者血清中显著高表达，提示miR-200c在氟致内皮细胞损伤过程中具有重要作用；研究表明氟中毒与氧化应激密切相关，氧化应激敏感蛋白p53可诱导miR-200c高表达，结合已有研究提出以下假说：过量氟引起内皮细胞ROS增加，氧化/抗氧化酶含量及活性异常，诱导高表达的p53转录调控miR-200c表达升高，靶基因NOS表达异常，引起内皮细胞功能损伤；而花青素是一种天然抗氧化剂，具有心血管保护及抗氧化作用，据此推测花青素可能对氟中毒具有保护作用，并通过拮抗氟诱导的p53/miR-200c高表达发挥其作用。

地方性氟中毒是我国重点防治的地方病之一，过量氟暴露可引起内皮细胞损伤导致心血管疾病的发生发展，但其机制尚不明确。以往研究主要探讨了氟致内皮细胞结构损伤，本研究以氟对内皮细胞功能影响为切入点，从疾病防治角度出发，探讨了花青素拮抗氟致内皮功能损伤的可能机制。本研究利用氟中毒动物模型及人脐静脉内皮细胞培养，探讨p53/miR-200c在氟致内皮细胞损伤中的作用及机制，以及花青素对氟中毒的拮抗作用。主要得出以下结果：a.在实验动物及细胞模型中观察到氟暴露可引起内皮细胞功能紊乱；b.氟暴露可引起内皮细胞氧化/抗氧化水平异常；c.p53低表达可拮抗氟致内皮细胞氧化应激及功能障碍；d.miR-200c参与p53对氟致内皮损伤的拮抗作用；e.花青素可缓解氟引起的内皮细胞氧化应激、功能紊乱及p53/miR-200c表达。综上，氟可通过诱导氧化应激引起内皮细胞功能紊乱，氧化应激敏感转录因子p53可调控氟中毒关键分子miR-200c的高表达，从而抑制其靶基因影响内皮功能。而花青素可发挥其抗氧化功能，减少p53/miR-200c的表达，拮抗氟致内皮损伤。