血管内皮细胞线粒体功能障碍在川崎病血管损伤早期的作用及新机制

Kawasaki Disease(KD) which is characterized by vasculitis is one of the high risk factors of coronary heart disease .Recently reported and our previous studies have confirmed that nucleus factor of activation of T cell(NFAT) play a role in the KD vascular injury. We found in the rabbit model of KD: mitochondrial swelling is earlier than endothelial injury in kawasaki disease; Mitochondria is the most sensitive organelles to the damage,and peroxisome proliferator-activated receptor gamma co-activator (PGC-1α) is the most important upstream factor to adjust the mitochondrial function.We hypothesize a new mechanism that PGC-1α targeting NFAT regulate endothelial cells damage in the early stage in patients with KD.The study design of the new mechanism is as follows:① To study the correlation between PGC-1α、 mitochondrial function and endothelial cells damage in patients with KD, and in animal models and cell models; ②To observe the influence of expressed NFAT when PGC-1α over expressed or silent expressed in endothelial cells,in order to analyze the mechanism that PGC-1α results in endothelial cell lesions by regulating the expression of NFAT; ③ To verify the hypothesis that PGC-1α can result in endothelial cell lesions and NFAT expression.This mechanism hypothesis, which has not been reported up to now, is a kind of original design that can provide new clues and potential therapeutic targets for KD.

以血管炎为特征的川崎病(Kawasaki Disease KD)是成年后冠心病的高危因素。最近报道且我们前期研究证实：活化T细胞核因子(NFAT)在KD血管损伤中发挥作用。我们在兔KD模型中发现：KD血管内皮细胞线粒体肿胀早于内皮细胞损伤；线粒体是对损伤最敏感的细胞器，而过氧化物酶体增殖物活化受体γ共激活因子-1α（PGC-1α）是其功能调节最重要的上游因子。因此我们设想: PGC-1α靶向NFAT调控血管内皮是KD血管早期损伤的新机制。本研究拟探讨： ①PGC-1α、线粒体功能与KD患儿血管内皮损伤、NFAT表达的相关性；②其过表达/表达沉默对离体血管内皮细胞/KD动物模型血管内皮细胞和NFAT表达的影响；③血管内皮细胞PGC-1α基因敲除后，对细胞生长、线粒体功能和NFAT表达的影响，以验证该机制，研究具有源头创新性，可为 KD 防治提供新线索和干预靶标。

以T细胞活化的全身性中小动脉炎是川崎病(Kawasaki Disease KD)的特征性表现，并且已经证实，川崎病长期存在的血管内皮损伤及内皮功能障碍是成年后冠心病的高危因素。我们前期研究证实:活化T细胞核因子(NFAT)在KD血管损伤中发挥重要调控作用。我们在兔KD模型中发现:KD血管内皮细胞线粒体肿胀早于内皮细胞损伤;线粒体是对损伤最敏感的细胞器，而过氧化物酶体增殖物活化受体γ共激活因子-1α(PGC-1α)是其功能调节最重要的上游因子。 因此我们提出了: PGC-1α靶向NFAT调控血管内皮是KD血管早期损伤的科学假说。本研究完成了1、PGC-1α与KD患儿血管内皮损伤、NFAT表达的临床研究;2PGC-1α过表达/表达沉默对离体血管内皮细胞及KD动物模型血管内皮细胞和NFAT表达的影响;3血管内皮细胞PGC-1α基因敲除后，对细胞生长、线粒体功能和NFAT表达的影响，基本完成PGC-1α靶向NFAT调控血管内皮功能的实验机制验证。