Irisin/PPARα通路介导HO-1抗动脉粥样硬化分子机制的研究

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.

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。

背景：动脉粥样硬化(Atherosclerosis, AS)发病率高，严重致死致残，但发病机制尚未完全阐明，使其防治成为难题。主要研究内容：1.分别从动物模型、细胞模型和慢病毒转染动物模型3个层面探索 Irisin/PPARα信号通路介导HO-1抗AS的作用及机制：1)探讨Irisin是否参与AS的病理过程及其与PGC-1α、PPARα和HO-1的相关性；2)阐述Irisin/PPARα激活HO-1抗AS的作用机制；3)通过病毒转染动物模型证实Irisin/PPARα/HO-1抗AS的作用。2.研究Irisin与冠心病的相关性。重要结果：1.与AS组比较，Irisin组内膜厚度、斑块面积显著减小(P＜0.05)，血清TC、TG、LDLC、MDA水平显著降低，NF-κB p65、CD36 mRNA和蛋白表达显著下调，而血清HDL-C水平、SOD活性显著升高(P＜0.05)。2.FNDC5组、FNDC5+GW6471组血管平滑肌细胞FNDC5、PPARα、HO-1、Bax/Bcl-2 mRNA和蛋白表达显著升高(均P＜0.05)，其增殖率和迁移率显著降低，而凋亡率显著升高(均P＜0.05)。3.FNDC5组、FNDC5+GW6471组平滑肌细胞或巨噬细胞FNDC5、PPARα及HO-1mRNA和蛋白表达显著增高(均P＜0.05)，胆固醇流出率显著增高(P＜0.05)；4. Irisin与冠心病严重临床类型、冠脉病变支数、冠脉狭窄程度、炎症因子水平负相关(均P＜0.05)。科学意义：证实Irisin参与AS、冠心病病理过程。首次证实Irisin/PPARα通过激活HO-1抑制氧化应激和炎症，调节血管平滑肌细胞增殖、迁移和凋亡，减少平滑肌细胞和巨噬细胞内脂质含量并促进胆固醇外流，抑制泡沫细胞形成，发挥抗AS作用。为延缓AS发生发展找到新的分子靶点，为Irisin相关药物的开发奠定理论、实验和临床基础。

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