普伐他汀改善股骨头缺血性坏死的内皮祖细胞机制

Microcirculation disturbance and impairment of vascular endothelial cells are the main causes of high-dose steroid-induced avascular necrosis of the femoral head (ANFH). Endothelial progenitor cells (EPCs) are demonstrated to play an important role during endothelium homeostasis and angiogenesis. Beyond the lipid-lowing effects: statins improve endothelial function, reduce vascular inflammation, and inhibit platelet aggregation and microcirculatory thrombus. In our preliminary experiments, it was found that EPCs number and function (migration and tube formation capacity) were reduced in ANFH rats when compared with control, which could be improved by pravastatin. This study is designed to investigate: (1) Whether dysfunction of EPCs is involved in the development of ANFH; (2) Whether dysfunction of EPCs could be improved by pravastatin in vivo and vitro; (3) Whether PI3K/Akt/mTOR signal pathway affects the beneficial effects of pravastatin on EPCs. Thus, to provide evidences for statins in the treatments of ANFH.

血管内皮损伤及微循环障碍在股骨头缺血性坏死（ANFH）的发病中起着关键作用。内皮祖细胞（EPCs）对稳定血管内膜、促进血管新生、改善缺血区域血供具有重要作用。他汀类药物除具有降脂作用外，还可修复受损内皮，抑制炎症反应和血栓沉积等。我们预实验发现：地塞米松联合脂多糖诱导大鼠ANFH模型4周后，骨髓来源EPCs存在增殖、迁移和小管形成功能障碍；在细胞水平，普伐他汀对地塞米松诱导的EPCs功能障碍具有改善作用。本项目拟在动物和细胞水平进行以下研究：（1）EPCs功能障碍是否参与了ANFH的病理过程；（2）普伐他汀对激素诱导的EPCs功能障碍是否具有改善作用；（3）普伐他汀改善EPCs功能，促进血管新生可能的机制（信号通路：PI3K/Akt/mTOR）。本课题的完成，将为临床使用他汀类药物治疗ANFH提供新的策略和依据。

研究背景：血管内皮损伤及微循环障碍在股骨头缺血性坏死（ANFH）的发病中起着关键作用。内皮祖细胞（EPCs）对稳定血管内膜、促进血管新生、改善缺血区域血供具有重要作用。他汀类药物除具有降脂作用外，还可修复受损内皮，抑制炎症反应和血栓沉积等。主要研究内容：ANFH的病理过程是否涉及EPCs功能障碍；普伐他汀对激素诱导EPCs功能障碍是否具有改善作用；普伐他汀改善EPCs功能，促进血管新生可能的机制(自噬与凋亡，信号通路AMPK/mTOR的研究。研究结论：ANFH存在EPCs数量减少和功能障碍；普伐他汀对Dex所诱导的EPCs数量减少和功能障碍具有改善作用，其机制涉及自噬和凋亡的调节，以及LKB1/AMPK/mTOR通路。本实验结果将为激素诱发EPCs的功能失调及ANFH的发病机理和防治提供新的思路。