Apela gene therapy alleviates pulmonary hypertension in rats

Abstract Pulmonary artery hypertension (PAH) is a common disease that threatens human health. At present, no treatment can cure PAH, and the prognosis is poor. Therefore, it is important to determine new targets for PAH treatment. Recently, a novel endogenous ligand Apela (ELABELA/Toddler/ELA32) of apelin peptide jejunum (APJ) receptor was identified as a possible PAH target. This study explored the potential effect of Apela gene therapy on rats with PAH. An AAV‐ELA32 recombinant expression vector was constructed by molecular cloning. Purified adeno‐associated virus (AAV) was injected into monocrotaline (MCT)‐induced PAH rats via tail vein 1 and 2 weeks after modeling. Apela gene therapy significantly reduced the increased right ventricular systolic pressure and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) in PAH rats. The results of histopathology and immunofluorescence showed that Apela gene therapy not only reduced the rate of pulmonary arteriole muscularization and media thickening in PAH rats but also inhibited the endothelial‐to‐mesenchymal transition of the pulmonary arteriole. Western blotting showed that Apela gene therapy up‐regulated the expression of KLF2/eNOs and BMPRII/SMAD4 in pulmonary arterioles of PAH rats. Overall, the results show that Apela gene therapy can inhibit pulmonary arteriolar vascular remodeling and reduce pulmonary artery pressure in PAH rats. These effects may be related to KLF2/eNOs and BMPRII/SMAD4 signaling pathways. The apelinergic system may be a potential new target for the prevention and treatment of PAH.