Warburg 效应介导PDGF促进肺动脉高压血管平滑肌细胞增殖及机制研究

Warburg effect has been shown to correlate with pulmonary arterial hypertension (PAH) vascular remodeling, but it is needed to further elucidate the role of Warburg effect and its regulators in proliferation of pulmonary artery vascular smooth muscle cells (VSMCs). We have found platelet derived growth factor (PDGF) induced proliferation of pulmonary artery VSMCs and significantly stimulated glucose flux through glycolysis. Therefore, we suppose that Warburg effect mediating pulmonary artery VSMCs proliferation induced by PDGF. To verify this issue, we generate PAH rats and pulmonary artery VSMCs to explore whether PDGF induces Warburg effect in pulmonary artery VSMCs, whether Warburg effect regulates PDGF-induced pulmonary artery VSMCs proliferation and which signal transduction pathway involved in connection between PDGF and Warburg effect. This investigation will thoroughly illustrate the regulation mechanism of Warburg effect and PDGF signal transduction pathway on proliferation of pulmonary artery VSMCs in PAH, which will lead to new theoretical basis and therapeutic targets for PAH treatment.

Warburg效应是多种肺动脉高压（PAH）发病分子机制的共同通路，是PAH治疗的潜在靶点；肺动脉血管平滑肌细胞（VSMCs）异常增殖是PAH血管重构的主要原因之一，Warburg效应是否导致PAH肺动脉VSMCs异常增殖尚不清楚。我们前期研究发现PDGF促进肺动脉VSMCs增殖伴有氧状态下乳酸合成增加，据此提出Warburg效应介导PDGF促进PAH肺动脉VSMCs增殖的假说。本课题拟利用PAH动物模型、PAH肺动脉VSMCs，分析PDGF受体相关信号通道阻滞、Warburg效应阻滞对PAH肺动脉VSMCs增殖和Warburg效应的影响，进一步了解Warburg效应是否介导 PDGF促进肺动脉VSMCs增殖，PDGF通过何信号转导通道调节肺动脉血管平滑肌细胞Warburg效应，从而揭示Warburg效应在PAH发生中的作用和机制。该研究有望进一步阐明PAH的发病机制，为其防治提供新靶点。

本课题通过使用野百合碱（MCT）成功建立肺动脉高压（PAH）大鼠模型，发现PAH大鼠肺组织和肺血管存在Warburg效应，且肺组织和肺血管血小板衍生生长因子（PDGF）及其受体，以及磷酸化的PDGF受体表达均上调；建模14天后，灌胃注入PDGF受体抑制剂伊马替尼（IM）和Warburg效应抑制剂二氯乙酸盐（DCA）14天，发现可以明显改善大鼠PAH表型，且IM可以显著抑制Warburg效应；为了进一步证明以上改变的机制，分离培养PAH的肺动脉平滑肌细胞（PASMCs），给予PDGF刺激6h后，加入PDGF受体抑制剂IM和索拉菲尼（SF），以及Warburg效应抑制剂DCA和2-脱氧-D-葡萄糖（2-DG），发现PDGF可以促进PASMCs增殖并增强其Warburg效应，而IM和SF可以逆转PASMCs增殖及Warburg效应，同时发现Warburg 效应介导PDGF 促进肺动脉高压PASMCs增殖的作用是通过PI3K/AKT/mTOR/HIF1α/PDK1信号通路来实现。综合上述结果，本研究为进一步阐明PAH的发病机制奠定了坚实的工作基础，为其防治提供了新靶点。项目资助发表SCI论文3篇，核心论文2篇，会议论文摘要3篇，1篇文章待发表。培养硕士生2名，且已经取得硕士学位。