Yijun Chen, Qianhui Zhang, Xi Chen, Yahe Xu, Jing Guo, Jiajia Meng, Mingjie Zhang, Bo Wang, Zhuoming Xu
Shanghai Children’s Medical Center and Shanghai Jiao Tong University School of Medicine.
China
International Journal of Biological Macromolecules
Int J Biol Macromol 2025;
DOI: 10.1016/j.ijbiomac.2025.146018
Abstract
Pulmonary arterial hypertension (PAH) is marked by elevated vascular resistance, right ventricular (RV) failure, and poor clinical outcomes. Current therapies primarily target pulmonary vascular hemodynamics, necessitating novel strategies to address RV remodeling. In this study, we investigated the role of lncRNA FGD5-AS1 and its micropeptides in PAH and RV remodeling, focusing on their effects on hyaluronic acid (HA) synthesis and extracellular matrix organization. FGD5-AS1 expression was significantly reduced in peripheral blood mononuclear cells of PAH patients and inversely correlated with HA levels and disease severity. Functional studies using FGD5-AS1 knockout (KO) in the AC16 human cardiomyocyte cell line led to upregulation of HAS2, increased HA production and activation of TLR4, contributing to pro-fibrotic and pro-hypertrophic responses. In a monocrotaline-induced PAH rat model, overexpression of FGD5-AS1 encoded micropeptide Pep1 reduced HA synthesis, suppressed heart failure biomarkers (NPPA, NPPB), and improved cardiac function, while Pep2 showed limited benefits. These findings demonstrate that FGD5-AS1 exerts protective effects in PAH by modulating HA synthesis through HAS2 regulation. The micropeptides, particularly Pep1, offer promising therapeutic potential for improving RV function and remodeling in PAH. This study highlights FGD5-AS1 and its derived micropeptides as novel therapeutic targets for PAH, providing new strategies to address RV dysfunction in this debilitating disease.
Category
Heart Dysfunction Associated with Pulmonary Vascular Disease (Right)
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes