Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, P.R. China.
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
Lab Invest. 2018 Oct;98(10):1333-1346. doi: 10.1038/s41374-018-0080-1. Epub 2018 May 22.
Dipeptidyl peptidase IV (DPP-4) is well known for its role in glucose homeostasis, and DPP-4 inhibitor (DPP-4i) exhibits multiple actions in cardiovascular diseases. However, the effect of DPP-4i on pulmonary hypertension (PH) remains unclear. Therefore, this study aims to investigate the effect of DPP-4i on pulmonary arterial remodeling in rats with PH and the potential underlying mechanisms. Our results show that DPP-4 was expressed in epithelial cells, endothelial cells, smooth muscle cells, and inflammatory cells in lung. DPP-4i (Sitagliptin) attenuated right ventricular systolic pressure (RVSP), right ventricle remodeling, hypertrophy of pulmonary arterial medial layer, inflammatory cell infiltration, and endothelial-mesenchymal transition (EndMT) in monocrotaline (MCT)-induced PH rats. Similarly, DPP-4i also alleviated bleomycin- and chronic hypoxia-induced PH in rats. In cultured human pulmonary arterial smooth muscle cells (PASMCs), DPP-4i inhibited platelet derived growth factor (PDGF)-BB-induced proliferation and migration, which was abolished by phosphatase and tensin homolog deleted on chromosome ten (PTEN) knockout. These results demonstrate that DPP-4 inhibition alleviates pulmonary arterial remodeling in experimental PH by inhibiting proliferation and migration of PASMCs.
二肽基肽酶 4（DPP-4）以其在葡萄糖稳态中的作用而闻名，DPP-4 抑制剂（DPP-4i）在心血管疾病中具有多种作用。然而，DPP-4i 对肺动脉高压（PH）的影响尚不清楚。因此，本研究旨在探讨 DPP-4i 对 PH 大鼠肺血管重塑的影响及其潜在机制。我们的结果表明，DPP-4 在肺的上皮细胞、内皮细胞、平滑肌细胞和炎症细胞中表达。DPP-4i（西他列汀）可减轻野百合碱诱导的 PH 大鼠的右心室收缩压（RVSP）、右心室重塑、肺动脉中层肥厚、炎性细胞浸润和内皮-间充质转化（EndMT）。同样，DPP-4i 还可减轻博来霉素和慢性低氧诱导的 PH 大鼠的 PH。在培养的人肺动脉平滑肌细胞（PASMCs）中，DPP-4i 抑制血小板衍生生长因子（PDGF-BB）诱导的增殖和迁移，该作用可被磷酸酶和张力蛋白同源物缺失的染色体 ten（PTEN）敲除所消除。这些结果表明，DPP-4 抑制通过抑制 PASMCs 的增殖和迁移来减轻实验性 PH 中的肺血管重塑。
