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Inhibition of KIR2.1 decreases pulmonary artery smooth muscle cell proliferation and migration. 2022
The investigation of effective therapeutic drugs for pulmonary hypertension (PH) is critical. KIR2.1 plays crucial roles in regulating cell proliferation and migration, and vascular remodeling. However, researchers have not yet clearly determined whether KIR2.1 participates in the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and its role in pulmonary vascular remodeling (PVR) also remains elusive. The present study aimed to examine whether KIR2.1 alters PASMC proliferation and migration, and participates in PVR, as well as to explore its mechanisms of action. For the in vivo experiment, a PH model was established by intraperitoneally injecting Sprague‑Dawley rats monocrotaline (MCT). Hematoxylin and eosin staining revealed evidence of PVR in the rats with PH. Immunofluorescence staining and western blot analysis revealed increased levels of the KIR2.1, osteopontin (OPN) and proliferating cell nuclear antigen (PCNA) proteins in pulmonary blood vessels and lung tissues following exposure to MCT, and the TGF‑β1/SMAD2/3 signaling pathway was activated. For the in vitro experiments, the KIR2.1 inhibitor, ML133, or the TGF‑β1/SMAD2/3 signaling pathway blocker, SB431542, were used to pre‑treat human PASMCs (HPASMCs) for 24 h, and the cells were then treated with platelet‑derived growth factor (PDGF)‑BB for 24 h. Scratch and Transwell assays revealed that PDGF‑BB promoted cell proliferation and migration. Immunofluorescence staining and western blot analysis demonstrated that PDGF‑BB upregulated OPN and PCNA expression, and activated the TGF‑β1/SMAD2/3 signaling pathway. ML133 reversed the proliferation and migration induced by PDGF‑BB, inhibited the expression of OPN and PCNA, inhibited the TGF‑β1/SMAD2/3 signaling pathway, and reduced the proliferation and migration of HPASMCs. SB431542 pre‑treatment also reduced cell proliferation and migration; however, it did not affect KIR2.1 expression. On the whole, the results of the present study demonstrate that KIR2.1 regulates the TGF‑β1/SMAD2/3 signaling pathway and the expression of OPN and PCNA proteins, thereby regulating the proliferation and migration of PASMCs and participating in PVR.
