Exosomal Long Noncoding RNA H19 as a Biomarker and Therapeutic Target in Atrial Fibrillation

Abstract

Although exosomal long noncoding RNAs (lncRNAs) have emerged as promising theragnostic targets in various diseases, their role in atrial fibrillation (AF) remains largely unexplored. Herein, we aimed to identify AF-specific serum exosomal lncRNAs and to evaluate their potential as theragnostic targets. RNA sequencing and qRT-PCR analyses consistently demonstrated significant downregulation of lncRNA H19 in serum exosomes of patients with AF compared with those without AF. Notably, serum exosomal lncRNA H19 levels showed significant diagnostic validity for AF and were closely associated with AF pathophysiology. In angiotensin II (Ang II)-treated iPSC- derived atrial cardiomyocytes, both loss- and gain-of-function experiments revealed that lncRNA H19 markedly modulated Ang II-induced hypertrophic responses, including increased expression of ANP, BNP, and beta-MHC, as well as enlargement of cell surface area. Moreover, in vivo experiments showed that cardiac-specific overexpression of lncRNA H19 significantly attenuated Ang II-induced cardiac dysfunction and hypertrophy (P < 0.05). Mechanistically, lncRNA H19 sponges miR-141-3p and miR-200a-3p, thereby regulating the PTEN pathway and contributing to cardiac hypertrophic remodeling and subsequent AF. Collectively, these findings identify a novel association between circulating exosomal lncRNA H19 and AF and further elucidate its mechanistic role in cardiac hypertrophy, highlighting its potential as a diagnostic biomarker and therapeutic target for AF.