MEK1/2抑制剂协同肝X受体激动剂促进动脉粥样硬化斑块稳定与消退

Atherosclerosis is a chronic pathology for coronary heart disease with disorders of lipid metabolism, inflammation and expression of microRNAs. Compared to prevention, the enhancement of atherosclerotic plaque stability and induction of lesion regression play more important roles for the patients. Activation of liver X receptor (LXR) by ligands can inhibit atherosclerosis and result in lesion regression. However, LXR ligands induce severe side effects, such as fatty liver and hypertriglyceridemia. We previously demonstrated that combination of MEK1/2 inhibitor and LXR ligand induced ABCA1 expression and inhibited atherosclerosis in a synergistic manner while eliminating the side effects. However, it remains unknown if the combination of MEK1/2 inhibitor and LXR ligand can enhance stability of lesion plaques and induce lesion regression as well as the involved mechanisms. In this propose, we will use proatherogenic mouse model to complete the following aims: 1) optimize the doses of MEK1/2 inhibitor and LXR ligand in stabilizing and regressing lesions; 2) investigate the mechanisms by which the combination of MEK1/2 inhibitor and LXR ligand function, such as the regulation of microRNAs expression and inflammation; 3) determine if the combination of MEK1/2 inhibitor and LXR ligand can induce a rapid lesion regression in the context of statin therapy; 4) collect serum and monocyte samples from patients of coronary heart disease and determine inflammatory factors and microRNAs levels; correlate clinical and basic results to identify new markers for the development of atherosclerosis. We anticipate that our study will discovery key targets for diagnosis/therapy in clinic and benefit drug design/development.

动脉粥样硬化是脂代谢、炎症及microRNAs参与的冠心病病理过程。与预防相比，促进斑块稳定与消退是临床上的理想目标。肝X受体(LXR)激动剂具有预防动脉粥样硬化和促进斑块消退功能，但引起严重的脂肪肝等副作用。我们前期研究发现低剂量MEK1/2抑制剂协同LXR激动剂刺激ABCA1表达、抑制动脉粥样硬化发生、消除LXR激动剂副作用。但组合是否对成熟斑块具有稳定和消退作用及机制不明。因此，我们拟采用模式动物完成：1. 优化组合药物剂量与配比对斑块的最佳稳定和消退作用; 2. MEK1/2抑制剂和LXR激动剂对参与血管重构的microRNAs、炎症分子等调控作用与机制; 3. 在他汀降脂基础上，确定MEK1/2抑制剂与LXR激动剂对斑块的快速消退和治疗的作用机制；4. 收集、分析动脉粥样硬化患者血清等样品并与模式动物结果关联，确定与动脉粥样硬化相关的重要标志物，为临床诊断和新药设计提供理论支持。

动脉粥样硬化是脂代谢紊乱、炎症及microRNAs共同参与的病理过程。在本项目执行过程中，我们证明了MEK1/2抑制剂协同LXR激动剂能够抑制动脉粥样硬化的发展，增强斑块稳定性，同时促进斑块的消退；机制上，我们发现组合药物能够上调内皮细胞和平滑肌细胞miR-126的表达，从而促进内皮修复，抑制黏附因子的表达和平滑肌细胞的钙化，进而增强斑块稳定性，最终发挥抗动脉粥样硬化作用；进一步研究发现组合药物能上调巨噬细胞ABCA1的表达，促进胆固醇外流，抑制巨噬细胞泡沫化，且MEK1/2抑制剂能通过激活肝脏AMPK来拮抗LXR激动剂的副作用；通过结合临床样本，确定了p-ERK1/2与临床血管病变间的密切联系，其可能有望作为动脉粥样硬化相关的重要标志物。总之，通过本项目的完成，我们确定了MEK1/2抑制剂协同LXR激动剂促进动脉粥样硬化斑块稳定与消退的作用和机制，同时结合临床样本分析为开发动脉粥样硬化的诊断试剂盒提供了潜在标志物。

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