JNK/MT信号通路在新型姜黄素衍生物C66预防高血糖引起的心肌损伤中的作用

Diabetic cardiomyopathy (DCM) impacts the living quality of patients seriously. Therefore, how to prevent and/or delay the development and progression of DCM urgently needs to be developed. Our previous study found that administration of novel curcumin analog, C66, prevented the development of DCM, inhibited the activity of c-Jun N-terminal kinase（JNK） and preserve the expression of metallothionein (MT) in cardiac tissues. Therefore, we hypothesized that C66 prevented the development of DCM via suppressing the activity of JNK, results in the restoration of MT expression. To confirm this hypothesis, the project will up regulate or down regulate the expression of JNK and MT in H9C2 cells using molecular biology technology, after which, the effect of C66 on high glucose-induced damage of H9C2 cells will be investigated and the expression of p-JNK、JNK、3-NT、4-HNE、TNF-α、PAI-1、CTGF、TGF-β、Caspase-3、MT in H9C2 cells will be detected. Furthermore, the JNK-KO, MT-TG and MT-KO transgenic mice will be used to further study the role of JNK/MT pathway cross-talk in the preventive effect of C66 on high glucose-caused cardiac damage. The study of this project will contribute to the elucidating the mechanism of C66 in DCM prevention and the finding of new target for DCM prevention. Therefore, it has important theoretical significance and application value.

糖尿病心肌病(DCM)严重影响患者的生活质量，如何预防DCM的发生和发展凾需迫切解决。前期研究工作中我们发现，姜黄素衍生物C66能预防DCM，并能抑制c-Jun氨基末端激酶（JNK）活性和恢复金属硫蛋白（MT）在糖尿病心肌中的表达。故我们推测C66可能通过抑制JNK的活化，恢复心肌细胞中MT的表达，从而发挥预防DCM的作用。为验证假说，本课题拟以H9C2细胞，应用分子生物学技术上调或抑制JNK、MT的表达，观察C66对高糖诱导的H9C2细胞损伤的影响，检测p-JNK、JNK、3-NT、4-HNE、TNF-α、PAI-1、CTGF、TGF-β、Caspase-3、MT等蛋白的表达；我们应用JNK-KO、MT-TG、MT-KO转基因小鼠，进一步研究JNK/MT信号通路在C66预防高糖引起的心肌损伤中的作用。本课题将阐明C66预防DCM的机制，探索DCM预防的新靶点，有重要的理论意义和应用价值。

糖尿病心肌病(DCM)严重影响患者的生活质量，如何预防DCM的发生和发展凾需迫切解决。前期研究工作中我们发现，姜黄素衍生物C66能预防DCM，并能抑制c-Jun氨基末端激酶（JNK）活性。故我们推测C66可能通过抑制JNK的活化，从而发挥预防DCM的作用。现有的研究证实JNK1与AKT相互拮抗在细胞凋亡中发挥着重要作用，为进一步探索JNK1在高糖诱导的心肌细胞损伤中的作用，以及验证C66是否主要通过对JNK1作用来发挥对糖尿病心肌病的保护作用。我们应用JNK1-/-转基因小鼠，进一步研究JNK/AKT信号通路在C66预防高糖引起的心肌损伤中的作用。本课题将阐明C66预防DCM的机制，探索DCM预防的新靶点，有重要的理论意义和应用价值。