Fatty acid-binding protein 5 aggravates pulmonary artery fibrosis in pulmonary hypertension secondary to left heart disease via activating wnt/β-catenin pathway

Introduction: Pulmonary hypertension secondary to left heart disease (PH-LHD) is a common and fatal disease. However, no effective therapeutic targets have been identified. Objectives: Here, we set out to illustrate the functional role and underlying mechanisms of fatty acid-binding protein 5 (FABP5) in PH-LHD development. Methods: We performed a systematic analysis of datasets GSE84704 and GSE16624 to identify differentially expressed genes and then constructed protein-protein interaction network for significant modules. Potential target genes in the modules were validated by RT-qPCR and western blot in a PH-LHD mouse model. PH-LHD or sham mice were treated with FABP5 antagonist SBFI-26 or DMSO for 28 days. The role of FABP5 on cardiac function was determined by echocardiography, its impact on pulmonary vascular remodelling were evaluated with right heart catheter, histological analysis and western blot. In vitro, primary pulmonary adventitial fibroblasts were used to investigate the pro-fibrotic mechanisms involving in FABP5. Results: FABP5 was the only one dramatically upregulated along with increased protein expression in the established PH-LHD mouse model. Inhibition of FABP5 by SBFI-26 injection abrogated pulmonary artery remodelling in PH-LHD and improved cardiac function. In vitro, SBFI-26 or FABP5 siRNA blunted the TGF beta 1-induced fibrotic response in cultured pulmonary adventitial fibroblasts. Mechanistically, FABP5 knockdown inhibited GSK3 beta phosphorylation and increased beta-catenin phosphorylation. The wnt/beta-catenin agonist SKL2001 diminished the antifibrotic effect of FABP5 knockdown on pulmonary adventitial fibroblasts under TGF-beta 1 stimulation. Conclusion: FABP5 is an important mediator of pulmonary artery remodelling and a potential therapeutic target for PH-LHD. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study reveals the significant role of fatty acid-binding protein 5 (FABP5) in pulmonary hypertension secondary to left heart disease (PH-LHD). Through experiments and in vitro studies, it was demonstrated that inhibiting FABP5 can improve pulmonary vascular remodeling and cardiac function. FABP5 may serve as a potential therapeutic target for PH-LHD.