Irisin/PPARα通路介导HO-1抗动脉粥样硬化分子机制的研究

近期研究表明，Irisin/PPARα信号通路、HO-1可调节脂肪代谢，改善肥胖和胰岛素抵抗，PPARα、HO-1可阻止动脉粥样硬化发生发展，并且irisin可能改善动脉粥样硬化，但irisin作为靶点抑制动脉粥样硬化进程的分子机制有待明确。本课题组前期研究发现，PPARα、HO-1有抗氧化和抗炎症作用，是二者抗动脉粥样硬化的重要机制。据此，我们假设，Irisin通过PPARα介导HO-1抗动脉粥样硬化。本课题将首先明确irisin在斑块中表达情况，及irisin、HO-1与泡沫细胞的相关性。其次，研究过表达irisin或shRNA下调irisin表达对泡沫细胞形成及胆固醇外流的影响，以及上调或下调HO-1、PPARα表达对irisin及相关因子的影响。最后，通过慢病毒转染动物模型证实irisin防治动脉粥样硬化的作用及机制。为开发irisin相关药物提供理论和实验依据。

Recently, several researches showed that fat metabolism is regulated by both the Irisin/PPARα signaling pathway and HO-1, which ameliorate the obesity and insulin resistance, and PPARα and HO-1 prevent the development of atherosclerosis. The investigations show that irisin may be able to inhibit the progression of atherosclerosis, but the underlying molecular mechanism is still unclear. The previous studies of our group revealed that PPARα or HO-1 participate in the process of antioxidant and anti-inflammatory, which plays an important role in anti-atherosclerosis of HO-1. It could be hypothesized that the anti-atherosclerotic effect of irisin is involved in HO-1 via PPARα. Therefore, the present study will firstly detect the expression of irisin in the plaques and the relationships among irisin, HO-1 and foam cells. Secondly, in order to explore the effect of irisin on the formation of foam cells and cholesterol efflux, the expression of irisin will be over-expressed or knock-down in cells. Thirdly the effect of the up or down-regulation of HO-1 or PPARα on the expression levels of irisin and related factors will be measured. Finally, above-mentioned action mechanisms will be confirmed at animal level by the transfection technology of irisin expression and RNA interference vectors in order to lay the theoretical and experimental foundation for the development development of irisin-associated drug.