黄芪多糖抑制p38α/NFκB信号通路介导的糖尿病心肌慢性炎症的机制研究

慢性炎症是糖尿病心肌病DCM发病的重要环节，p38α/NFκB信号通路介导的糖尿病心肌慢性炎症是DCM的重要发病机制。我们前期研究证实黄芪多糖APS能显著改善DCM；进一步的研究发现，APS能降低糖尿病心肌p38α和NFκB的表达活性、降低其p38α磷酸化位点Thr180和Tyr182的磷酸化水平，而过表达p38α能逆转APS对糖尿病心肌炎症浸润和胶原纤维沉积的改善作用、逆转APS对糖尿病心肌NFκB表达的下调作用，提示APS可改善糖尿病心肌慢性炎症损伤，p38α为其作用靶点；然而确切的机制尚不清楚。本课题以心肌p38α磷酸化位点（Thr180和Tyr182）突变激活或失活的小鼠和细胞为模型，深入探讨APS通过下调心肌p38α磷酸化水平对糖尿病心肌慢性炎症的改善作用，阐明APS抑制糖尿病心肌p38α/NFκB信号通路的调控机制，为APS应用于DCM的临床治疗提供确切的理论依据和实验基础。

The cardiac inflammation induced by p38α/NFkB signaling plays an important role in the pathogenesis of diabetic cardiomyopathy (DCM). Our previous studies showed that Astragalus polysaccharides (APS) treatment prevented myocardial ultrastructure abnormality and cardiac dysfunction in diabetic mice. However, the exact mechanism of the beneficial effect of APS on DCM is still unknown. We further found that APS treatment led to less cardiac protein expression of p38α, NFκB, p38α-Thr180, and p38α-Tyr182 in diabetic mice. Moreover, we found that the inhibition of APS treatment on the NFκB protein expression, the inflammatory infiltration and collagen deposition in diabetic hearts could all be prevented by the cardiac p38α overexpression in diabetic mice. Our data indicated the important role of p38α in the improvement of APS treatment on the cardiac inflammation in diabetes. Therefore, in the current study, we will use the diabetic mice and cardiac myocytes with the activated or inactivated mutation of the p38α phosphorylation site, to explore the role of APS on the regulation of p38α phosphorylation and p38α/NF-kB signaling-induced inflammation in DCM. This study may provide further rationale and more evidence for the APS treatment on DCM.