Combined inhibition of FABP4/5 ameliorates pulmonary hypertension by reducing pulmonary vascular and right ventricular fibrosis

Lipid metabolism disorder is increasingly recognized as hallmarks of Pulmonary hypertension (PH). Fatty acid-binding proteins (FABPs), particularly FABP4 and FABP5, which regulate lipid transport and metabolism of fatty acid, are thought to contribute to the development of PH. However, it remains unclear whether FABP4 and FABP5 serve as therapeutic targets for the treatment of PH. In the present study, the levels of FABP4/5 were elevated in the plasma and lung tissues of IPAH patients, as well as in the lung tissues of the PH rat model compared with control. The circulating levels of FABP4 of IPAH patients were correlated with mean pulmonary arterial pressure (mPAP). To determine the preventive or therapeutic effect of FABP4 and FABP5 inhibition, FABP4 and FABP5 inhibitors alone or combination were administered at early (days 2 following monocrotaline (MCT) injection) and late (day 12 following MCT injection) stage of PH rat model, respectively. Combined treatment with FABP4/5 inhibitors in the early stage of the MCT-PH rat model effectively reduced right ventricular systolic pressure (RVSP) and improved right ventricular function, accompanied by reductions in pulmonary vascular and right ventricular fibrosis, as well as blood lipid levels, lipid peroxidation, and inflammation. Combined treatment with FABP4/5 inhibitors at the late stage of MCT-PH improved right ventricular function, suppressed pulmonary vascular and right ventricular fibrosis, and lowered blood lipid levels, but did not affect RVSP. In conclusion, our study indicates that combined inhibition of FABP4 and FABP5 can prevent the pathogenesis of PH, representing a potential therapeutic strategy for PH.