DNA拓扑异构酶II抑制剂促进动脉粥样硬化斑块消退

Regression of atherosclerotic lesions is a positive and an important procedure for the repair of endothelial injury and vascular remodeling. The migration of lipid-laden macrophages (foam cells) from the sites of lesions, which is a critical step in the regression, is mediated by a chemokine receptor, CCR7, and its ligands. DNA topoisomerase II (Topo II) demonstrates multiple functions in cancer biology and immunology. In our previous study, we observed that Topo II inhibitors induced macrophage ABCA1 and ABCG1 expression (both are anti-atherogenic), inhibited expression of the receptor for oxLDL, and enhanced reverse cholesterol transport in vivo. In vitro, we observed that Topo II inhibitors regulated expression of SIRT1 and CCR7. Taken together, our results indicate that Topo II can play an important role in regression of atherosclerotic lesions. Therefore, in this proposal, we suggest to investigate if Topo II inhibitors can promote the regression of lesions by completing a series of both cellular and animal studies. At the mechanistic levels, we will determine if the alteration of Topo II activity can regulate expression of SIRT1, CCR7 and its ligands as well as the involved mechanisms; determine the role of Topo II activity in the differentiation and migration of lipid-laden macrophages and if these functions are related to regulation of SIRT1 and CCR7 expression. By completing these studies, we can unveil the effects and mechanisms of Topo II inhibitors on expression of genes for the regression, and the new role of Topo II in cardiovascular system. We believe that our study can provide new theories and targets for regression of atherosclerosis.

动脉粥样硬化斑块消退是积极、重要的血管修复与重塑过程，巨噬细胞等从斑块中迁出是消退的关键并主要由CCR7及配体驱动。DNA拓扑异构酶II (Topo II) 在肿瘤、免疫中起重要作用。我们在前期研究中发现Topo II抑制剂刺激巨噬细胞抗动脉粥样硬化基因ABCA/G1表达并抑制oxLDL受体的表达，促进体内胆固醇逆转运；我们还发现抑制Topo II刺激SIRT1和CCR7表达，预示Topo II极有可能在斑块消退中发挥作用。为此我们拟在细胞和动物水平上研究抑制Topo II促进斑块消退的作用。机制上,研究改变Topo II活性对SIRT1和CCR7及配体表达与信号通路；明确Topo II活性对荷脂巨噬细胞表型、迁移能力的改善作用以及与SIRT1和CCR7的关联性，对斑块消退相关基因的调控机理；明确Topo II活性在心血管系统中的新功能，为动脉硬化斑块消退提供新思路与干预靶点。

动脉粥样硬化斑块消退是积极、重要的血管修复与重塑过程，受到多种因素调控。在本项目执行中，我们完成了DNA拓扑异构酶II抑制剂对动脉粥样硬化及动脉粥样硬化血管钙化的防治作用；机制上我们发现：1) DNA拓扑异构酶II抑制剂以LXR依赖的方式上调CETP的表达，从而改善血脂水平；2) DNA拓扑异构酶II抑制剂以LXR依赖方式上调巨噬细胞与平滑肌细胞ABCA1与ABCG1的表达，促进胆固醇逆转运，说明DNA拓扑异构酶II 抑制剂能够激活LXR从而发挥调控作用，这与我们之前发现的对CCR7的调控相一致；3) DNA拓扑异构酶II抑制剂通过上调p53和miR-203-3p、抑制BMP2表达，抑制血管平滑肌细胞的成骨分化，从而减少血管钙化，增加动脉粥样硬化斑块稳定性；4) DNA拓扑异构酶II抑制剂通过上调miR-21表达，诱导平滑肌细胞向收缩表型转换，抑制内膜增生。总之，通过对本项目计划书中研究内容的完成，我们明确了DNA拓扑异构酶II活性在心血管系统中的新功能，为动脉硬化斑块稳定性与斑块消退提供新思路与干预靶点。