1. Academic Validation
  2. Pyruvate kinase M2 activation protects against the proliferation and migration of pulmonary artery smooth muscle cells

Pyruvate kinase M2 activation protects against the proliferation and migration of pulmonary artery smooth muscle cells

  • Cell Tissue Res. 2020 Dec;382(3):585-598. doi: 10.1007/s00441-020-03245-2.
Aikai Zhang 1 Fenfang Yu 2 Wande Yu 1 Peng Ye 1 Pengfei Liu 1 Yue Gu 1 Shaoliang Chen 1 Hang Zhang 3
Affiliations

Affiliations

  • 1 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, China.
  • 2 Department of Respiratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, China.
  • 3 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, China. dxh_nari@sina.com.
Abstract

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.

Keywords

Migration; Proliferation; Pulmonary artery hypertension; Pulmonary artery smooth muscle cells; Pyruvate kinase M2.

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