Functional Roles of CD26/DPP4 in Bleomycin-Induced Pulmonary Hypertension Associated with Interstitial Lung Disease

• Published in: International journal of molecular sciences 2024-01, Vol.25 (2), p.748
• Main Authors: Okaya, Tadasu, Kawasaki, Takeshi, Sato, Shun, Koyanagi, Yu, Tatsumi, Koichiro, Hatano, Ryo, Ohnuma, Kei, Morimoto, Chikao, Kasuya, Yoshitoshi, Hasegawa, Yoshinori, Ohara, Osamu, Suzuki, Takuji
• Format: Article
• Language: English
• Subjects: Animals; Bleomycin; Bleomycin - toxicity; CD26; Cell growth; Cytotoxicity; Dipeptidyl Peptidase 4 - genetics; dipeptidyl peptidase-4; Genes; Heart enlargement; Humans; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - genetics; interstitial lung disease; Lung diseases; Lung Diseases, Interstitial - chemically induced; Lung Diseases, Interstitial - genetics; Lungs; Mice; Mice, Knockout; Osteochondrodysplasias; Pathogenesis; Phosphatidylinositol 3-Kinases; Pulmonary arteries; Pulmonary hypertension; RNA; Scientific equipment and supplies industry; Sitagliptin; Smooth muscle; Transforming Growth Factor beta - genetics; Transforming growth factors; Veins & arteries
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25020748

Pulmonary hypertension (PH) with interstitial lung diseases (ILDs) often causes intractable conditions. CD26/Dipeptidyl peptidase-4 (DPP4) is expressed in lung constituent cells and may be related to the pathogenesis of various respiratory diseases. We aimed to clarify the functional roles of CD26/DPP4 in PH-ILD, paying particular attention to vascular smooth muscle cells (SMCs). knockout ( KO) and wild type (WT) mice were administered bleomycin (BLM) intraperitoneally to establish a PH-ILD model. The BLM-induced increase in the right ventricular systolic pressure and the right ventricular hypertrophy observed in WT mice were attenuated in KO mice. The BLM-induced vascular muscularization in small pulmonary vessels in KO mice was milder than that in WT mice. The viability of TGFβ-stimulated human pulmonary artery SMCs (hPASMCs) was lowered due to the knockdown with small interfering RNA. According to the results of the transcriptome analysis, upregulated genes in hPASMCs with TGFβ treatment were related to pulmonary vascular SMC proliferation via the Notch, PI3K-Akt, and NFκB signaling pathways. Additionally, knockdown in hPASMCs inhibited the pathways upregulated by TGFβ treatment. These results suggest that genetic deficiency of protects against BLM-induced PH-ILD by alleviating vascular remodeling, potentially through the exertion of an antiproliferative effect via inhibition of the TGFβ-related pathways in PASMCs.