Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, China.
Department of Respiratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, China.
Cell Tissue Res. 2020 Dec;382(3):585-598. doi: 10.1007/s00441-020-03245-2. Epub 2020 Jul 27.
Pyruvate kinase M2 (PKM2), which is encoded by PKM, is a ubiquitously expressed intracellular protein and is associated with proliferation cell phenotype. In PAH patients and PAH models, we found higher levels of PKM2 tyrosine 105 phosphorylation (phospho-PKM2 (Y105)) than in controls, both in vivo and in vitro. Here, we demonstrate that PKM2 stimulates inflammatory and apoptosis signalling pathways in pulmonary artery smooth muscle cells (PASMCs) and promotes PASMC migration and proliferation. PKM2 phosphorylation promoted the dimerization activation and nuclear translocation of STAT3, a transcription factor regulating proliferation, growth, and apoptosis. TLR2, a transmembrane protein receptor involved in both innate and adaptive immune responses, promoted PKM2 phosphorylation in hypoxia-induced PASMCs. Therefore, we hypothesized that PKM2 also affects the proliferation and migration of PASMCs. The proliferation of hypoxia-induced normal human pulmonary artery smooth muscle cells (normal-HPASMCs) was found to be inhibited by TEPP-46 (PKM2 agonist) and PKM2 siRNA using wound healing, 5-ethynyl-2'-deoxyuridine (EdU), and immunofluorescence (Ki67) assays. PASMCs isolated from PAH patients (PAH-HPASMCs) and hypoxia-treated rats (PAH-RPASMCs) also confirmed the above results. TEPP-46 treatment was found to improve hypoxia-induced pulmonary artery remodelling and right heart function in mice, and the link between PKM2 and STAT3 was also confirmed in vivo. In conclusion, PKM2 plays crucial roles in the proliferation and migration of PASMCs.
丙酮酸激酶 M2（PKM2）由 PKM 编码，是一种广泛表达的细胞内蛋白，与增殖细胞表型相关。在 PAH 患者和 PAH 模型中，我们发现 PKM2 酪氨酸 105 磷酸化（磷酸化-PKM2（Y105））水平高于对照组，无论是在体内还是体外。在这里，我们证明 PKM2 可刺激肺动脉平滑肌细胞（PASMC）中的炎症和凋亡信号通路，并促进 PASMC 的迁移和增殖。PKM2 磷酸化促进 STAT3 的二聚化激活和核易位，STAT3 是调节增殖、生长和凋亡的转录因子。TLR2 是一种参与固有和适应性免疫反应的跨膜蛋白受体，可促进低氧诱导的 PASMC 中 PKM2 的磷酸化。因此，我们假设 PKM2 也会影响 PASMC 的增殖和迁移。发现缺氧诱导的正常人类肺动脉平滑肌细胞（normal-HPASMCs）的增殖被 TEPP-46（PKM2 激动剂）和 PKM2 siRNA 通过划痕愈合、5-乙炔基-2'-脱氧尿苷（EdU）和免疫荧光（Ki67）测定抑制。从 PAH 患者（PAH-HPASMCs）和缺氧处理的大鼠（PAH-RPASMCs）分离的 PASMCs 也证实了上述结果。TEPP-46 治疗可改善小鼠缺氧诱导的肺动脉重塑和右心功能，体内也证实了 PKM2 和 STAT3 之间的联系。总之，PKM2 在 PASMC 的增殖和迁移中起关键作用。
