血小板衍生的 TGF-β1 通过上调 PKM2（丙酮酸激酶肌肉同工酶 2）增强肺动脉平滑肌细胞的有氧糖酵解。
Platelet-Derived TGF (Transforming Growth Factor)-β1 Enhances the Aerobic Glycolysis of Pulmonary Arterial Smooth Muscle Cells by PKM2 (Pyruvate Kinase Muscle Isoform 2) Upregulation.
机构信息
Department of Pharmacology, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (Y.Z., D.S., X.G., M.L., X.-B.Z., J.G., Y.W.G., L.L., R.M., Z.-Y.M.).
The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Y.Z., D.S., X.G., M.L., X.-B.Z., J.G., Y.W.G., L.L., R.M., Z.-Y.M.).
出版信息
Hypertension. 2022 May;79(5):932-945. doi: 10.1161/HYPERTENSIONAHA.121.18684. Epub 2022 Mar 2.
BACKGROUND
Metabolic reprogramming is a hallmark of pulmonary arterial hypertension. Platelet activation has been implicated in pulmonary arterial hypertension (PAH), whereas the role of platelet in the pathogenesis of PAH remains unclear.
METHODS
First, we explored the platelet function of semaxanib' a inhibitor of VEGF receptor (SU5416)/hypoxia mice and monocrotaline-injected rats PAH model. Then we investigated pulmonary arterial smooth muscle cell aerobic glycolysis after being treated with platelet supernatant. TGF (transforming growth factor)-βRI, pyruvate kinase muscle 2, and other antagonists were applied to identify the underlying mechanism. In addition, platelet-specific deletion TGF-β1 mice were exposed to chronic hypoxia and SU5416. Cardiopulmonary hemodynamics, vascular remodeling, and aerobic glycolysis of pulmonary arterial smooth muscle cell were determined.
RESULTS
Here, we demonstrate that platelet-released TGF-β1 enhances the aerobic glycolysis of pulmonary arterial smooth muscle cells after platelet activation via increasing pyruvate kinase muscle 2 expression. Mechanistically, platelet-derived TGF-β1 regulate spyruvate kinase muscle 2 expression through mTOR (mammalian target of rapamycin)/c-Myc/PTBP-1(polypyrimidine tract binding protein 1)/hnRNPA-1(heterogeneous nuclear ribonucleoprotein A1) pathway. Platelet TGF-β1 deficiency mice are significantly protected from SU5416 plus chronic hypoxia-induced PAH, including attenuated increases in right ventricular systolic pressure and less pulmonary vascular remodeling. Also, in mice, pulmonary arterial smooth muscle cells showed lower glycolysis capacity and their pyruvate kinase muscle 2 expression decreased.
CONCLUSIONS
Our data demonstrate that TGF-β1 released by platelet contributes to the pathogenesis of PAH and further highlights the role of platelet in PAH.
背景
代谢重编程是肺动脉高压的一个标志。血小板激活已被认为与肺动脉高压（PAH）有关，而血小板在 PAH 发病机制中的作用尚不清楚。
方法
首先，我们研究了 semaxanib（一种血管内皮生长因子受体（VEGF 受体）抑制剂）/缺氧小鼠和野百合碱注射大鼠 PAH 模型中的血小板功能。然后，我们研究了血小板上清液处理后肺动脉平滑肌细胞的有氧糖酵解。应用 TGF-βRI、丙酮酸激酶肌肉 2 及其他拮抗剂来确定潜在的机制。此外，血小板特异性缺失 TGF-β1 的小鼠暴露于慢性缺氧和 SU5416 中，测定心肺血流动力学、肺动脉平滑肌细胞血管重构和有氧糖酵解。
结果
在这里，我们证明血小板释放的 TGF-β1 通过增加丙酮酸激酶肌肉 2 的表达，增强血小板激活后肺动脉平滑肌细胞的有氧糖酵解。在机制上，血小板衍生的 TGF-β1 通过 mTOR（哺乳动物雷帕霉素靶蛋白）/c-Myc/PTBP-1（多嘧啶 tract 结合蛋白 1）/hnRNPA-1（异质核核糖核蛋白 A1）通路调节丙酮酸激酶肌肉 2 的表达。血小板 TGF-β1 缺乏小鼠对 SU5416 加慢性缺氧诱导的 PAH 有明显的保护作用，包括右心室收缩压升高减少和肺血管重构减少。此外，在 TGF-β1 缺陷小鼠中，肺动脉平滑肌细胞的糖酵解能力较低，其丙酮酸激酶肌肉 2 的表达减少。
结论
我们的数据表明，血小板释放的 TGF-β1 有助于 PAH 的发病机制，并进一步强调了血小板在 PAH 中的作用。
Zotero 插件