Transcriptome 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 hy-poxic PH remains unknown. Therefore, we aimed to clarify the mechanistic role of CD26/DPP4 in lung fibroblasts in hypoxic PH. Dpp4 knockout (Dpp4 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 Dpp4 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 TGFB2, TGFB3, and TGFA were all upregulated as differentially expressed genes after DPP4 knockdown with small interfering RNA treatment. These results suggest that CD26/DPP4 plays a suppressive role in TGFß signal-regulated fibroblast ac-tivation under hypoxic conditions. Therefore, CD26/DPP4 may be a potential therapeutic target in patients with PH associated with chronic hypoxia. Overall design: To explore the potential effects of CD26/DPP4 on HLFs under hypoxic conditions, we performed RNA sequencing of HLFs treated with negative control siRNA (Control) or DPP4-siRNA (DPP4 KD) cultured under normoxic or hypoxic conditions.