Suzuki Yuri, Kawasaki Takeshi, Tatsumi Koichiro, Okaya Tadasu, Sato Shun, Shimada Ayako, Misawa Tomoko, Hatano Ryo, Morimoto Chikao, Kasuya Yoshitoshi, Hasegawa Yoshinori, Ohara Osamu, Suzuki Takuji
Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University, Chiba 260-8670, Japan.
Int J Mol Sci. 2024 Nov 23;25(23):12599. doi: 10.3390/ijms252312599.
In hypoxic pulmonary hypertension (PH), pulmonary vascular remodeling is characterized by the emergence of activated adventitial fibroblasts, leading to medial smooth muscle hyperplasia. Previous studies have suggested that CD26/dipeptidyl peptidase-4 (DPP4) plays a crucial role in the pathobiological processes in lung diseases. However, its role in pulmonary fibroblasts in hypoxic PH remains unknown. Therefore, we aimed to clarify the mechanistic role of CD26/DPP4 in lung fibroblasts in hypoxic PH. knockout ( KO) and wild-type (WT) mice were exposed to hypoxia for 4 weeks. The degree of PH severity and medial wall thickness was augmented in KO mice compared with that in WT mice, suggesting that CD26/DPP4 plays a suppressive role in the development of hypoxic PH. Transcriptome analysis of human lung fibroblasts cultured under hypoxic conditions revealed that , , and were all upregulated as differentially expressed genes after knockdown with small interfering RNA treatment. These results suggest that CD26/DPP4 plays a suppressive role in TGFβ signal-regulated fibroblast activation under hypoxic conditions. Therefore, CD26/DPP4 may be a potential therapeutic target in patients with PH associated with chronic hypoxia.
在缺氧性肺动脉高压（PH）中，肺血管重塑的特征是活化的外膜成纤维细胞出现，导致中层平滑肌增生。先前的研究表明，CD26/二肽基肽酶-4（DPP4）在肺部疾病的病理生物学过程中起关键作用。然而，其在缺氧性PH的肺成纤维细胞中的作用仍不清楚。因此，我们旨在阐明CD26/DPP4在缺氧性PH的肺成纤维细胞中的作用机制。将基因敲除（KO）小鼠和野生型（WT）小鼠暴露于缺氧环境4周。与WT小鼠相比，KO小鼠的PH严重程度和中层壁厚增加，表明CD26/DPP4在缺氧性PH的发展中起抑制作用。对在缺氧条件下培养的人肺成纤维细胞进行转录组分析发现，在用小干扰RNA处理敲低 后， 、 和 均作为差异表达基因上调。这些结果表明，CD26/DPP4在缺氧条件下对TGFβ信号调节的成纤维细胞活化起抑制作用。因此，CD26/DPP4可能是慢性缺氧相关PH患者的潜在治疗靶点。
