BDNF 对2型糖尿病冠状动脉粥样硬化炎症的调控作用及机制研究

Coronary atherosclerosis (CAS) is an important complication for type II diabetes and major leading cause of death in patients with diabetes. Due to the limitation on our understanding of the pathogenesis of coronary atherosclerosis, the treatments are unsatisfied. Our preliminary studies indicated that the levels of brain-derived neurotrophic factor (BDNF) were reduced significantly in the serum of type II diabetic patients with small vessel disease, and BDNF inhibited inflammation by modulating M1/M2 differentiation of macrophages. In the current study, we revealed that knockdown of BDNF enhanced M1 differentiation of which suggested that BDNF increase the lipid uptake in macrophage by inducing M1 macrophage. Therefore, we hypothesized that BDNF suppress type II diabetes associated coronary atherosclerosis through down regulation of inflammation, resulting in improving angiogenesis and vascular disease repair. This project will investigate the protective effect and underlying mechanisms of BDNF in diabetic vascular disease from molecular, cellular, and systemic levels. Successful completion of this study may provide experimental support for developing a novel immunotherapeutic approach for diabetes and its vascular complications.

冠状动脉粥样硬化（CAS）是 2型糖尿病的重要并发症及导致患者死亡的主要原因。炎症在2型糖尿病CAS发生发展中起着重要的作用，但具体机制不详。我们前期研究结果表明：2型糖尿病伴有小血管并发症的患者血清中BDNF水平显著降低，BDNF 可通过调节巨噬细胞 M1/M2平衡降低炎症。预实验结果发现BDNF敲减可促进M1分化，亦即BDNF抑制巨噬细胞向M1分化，进而诱导成M1型巨噬细胞，而M1型内脂质高于M2型，从而增强了巨噬细胞的脂质摄取能力。因此我们推测“BDNF通过下调炎症反应抑制2型糖尿病CAS的发生，进而改善新生血管的形成和促进血管性损害的修复”。本研究拟应用分子和细胞生物学等技术，从临床材料、动物实验和细胞水平3个层次探讨 BDNF调控糖尿病CAS的潜在作用和相关机制，为寻求全新的2型糖尿病CAS的治疗策略提供理论基础和重要实验依据。

已证明 M2 巨噬细胞极化在糖尿病（DM）中的动脉粥样硬化。此外，前列腺素 E2 (PGE2)参与 M2 巨噬细胞极化的发展。因此，研究目的探讨PGE2在糖尿病冠状动脉粥样硬化（DMAS）中M2巨噬细胞极化的具体机制。最初，临床样本是获得并建立DMAS小鼠模型。 BDNF 的表达为确定，并评估 M1 和 M2 巨噬细胞极化。然后，DMAS 小鼠和血清指示剂中 BDNF 和 PGE2 的水平被改变，动脉粥样硬化斑块、PBMC 以及 M1 和 M2 巨噬细胞对脂质的吸收极化确定。分离巨噬细胞和 PGE2 的作用CREB/BDNF/TrkB 信号通路对 M2 巨噬细胞极化探索了。 BDNF被下调，巨噬细胞分化为M1在 DMAS 患者和小鼠中。观察到 BDNF 和 PGE2 促进 M2 巨噬细胞极化，其中 PBMC 的动脉粥样硬化斑块和脂质摄取减少，并且 DMAS 在小鼠中得到缓解。 BDNF 的过表达激活了CREB/BDNF/TrkB 信号通路和刺激的 M2 巨噬细胞极化在巨噬细胞中。 PGE2 通过诱导 KLF4 刺激 M2 巨噬细胞极化通过激活 CREB/BDNF/TrkB 信号通路。本研究表明 PGE2 通过激活 CREB/ 促进 M2 巨噬细胞极化。BDNF/TrkB 信号通路，从而缓解 DMAS。