Department of Physiology, Shihezi University Medical College, Shihezi, Xinjiang 832002, P.R. China.
Department of Ultrasound, the First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang 832002, P.R. China.
Int J Mol Med. 2022 Sep;50(3). doi: 10.3892/ijmm.2022.5175. Epub 2022 Jul 20.
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 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 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.
肺高血压（PH）的有效治疗药物的研究至关重要。KIR2.1 在调节细胞增殖和迁移以及血管重塑中起着至关重要的作用。然而，研究人员尚未明确确定 KIR2.1 是否参与肺动脉平滑肌细胞（PASMC）的增殖和迁移，其在肺血管重塑（PVR）中的作用也仍不清楚。本研究旨在探讨 KIR2.1 是否改变 PASMC 的增殖和迁移，并参与 PVR，以及探讨其作用机制。在实验中，通过腹腔注射野百合碱（MCT）建立 PH 模型。苏木精和伊红染色显示 PH 大鼠存在 PVR 的证据。免疫荧光染色和 Western blot 分析显示，MCT 暴露后，肺血管和肺组织中 KIR2.1、骨桥蛋白（OPN）和增殖细胞核抗原（PCNA）蛋白水平升高，TGF-β1/SMAD2/3 信号通路被激活。在实验中，使用 KIR2.1 抑制剂 ML133 或 TGF-β1/SMAD2/3 信号通路抑制剂 SB431542 预处理人 PASMC（HPASMC）24 h，然后用血小板衍生生长因子（PDGF）-BB 处理 24 h。划痕和 Transwell 实验表明，PDGF-BB 促进细胞增殖和迁移。免疫荧光染色和 Western blot 分析表明，PDGF-BB 上调 OPN 和 PCNA 表达，并激活 TGF-β1/SMAD2/3 信号通路。ML133 逆转了 PDGF-BB 诱导的增殖和迁移，抑制了 OPN 和 PCNA 的表达，抑制了 TGF-β1/SMAD2/3 信号通路，并减少了 HPASMC 的增殖和迁移。SB431542 预处理也减少了细胞增殖和迁移；然而，它并不影响 KIR2.1 的表达。总的来说，本研究结果表明，KIR2.1 调节 TGF-β1/SMAD2/3 信号通路以及 OPN 和 PCNA 蛋白的表达，从而调节 PASMC 的增殖和迁移，并参与 PVR。
