biostudies-literatureSuzuki YIntractable Respiratory Diseases and Pulmonary Hypertension Research Group, Ministry of Health, Labor and Welfare, JapanChiba University School of MedicineAMED-CRESTJSPS KAKENHIAMEDGSK Japan Researchthe Initiative for Realizing Diversity in the Research EnvironmentGSK Japan Research Grant 2019Therapeutics Research Initiative Grant from Chiba University School of MedicineInitiative for Realizing Diversity in the Research Environment; and a research grant from the In-tractable Respiratory Diseases and Pulmonary Hypertension Research Group, Ministry of Health, Labor and Welfare, Japan12599https://www.ebi.ac.uk/biostudies/studies/S-EPMC11640941biostudies-literatureUnknown25(23)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. <i>Dpp4</i> knockout (<i>Dpp4</i> 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 <i>Dpp4</i> 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 <i>TGFB2</i>, <i>TGFB3</i>, and <i>TGFA</i> were all upregulated as differentially expressed genes after <i>DPP4</i> 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.International journal of molecular sciencesTranscriptome Analysis of Fibroblasts in Hypoxia-Induced Vascular Remodeling: Functional Roles of CD26/DPP4.PMC11640941JP21gm1210003, JP23gm181000924K1910222K1616323FC1031A-519K17663, 22K16163, 22H03076, 24K1910219K17663JP24gm181000920FC1027, 23FC103122H03076223fa627003h2019 A-5243fa627003hJP21gm12100032019-G620FC1027Kawasaki TKasuya YSuzuki TTatsumi KHasegawa YOkaya TSato SMorimoto CHatano ROhara OSuzuki YShimada AMisawa TfalseTranscriptome Analysis of Fibroblasts in Hypoxia-Induced Vascular Remodeling: Functional Roles of CD26/DPP4.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. <i>Dpp4</i> knockout (<i>Dpp4</i> 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 <i>Dpp4</i> 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 <i>TGFB2</i>, <i>TGFB3</i>, and <i>TGFA</i> were all upregulated as differentially expressed genes after <i>DPP4</i> 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.2024-01-01T00:00:00Z2024 Nov2026-05-26T20:10:52.969Z2025-04-04T01:26:05.956ZS-EPMC116409413968431110.3390/ijms252312599