Prostaglandin I2 signaling prevents angiotensin II-induced atrial remodeling and vulnerability to atrial fibrillation in mice

Abstract Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I₂ (PGI₂) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I₂ receptor (IP). However, the role of PGI₂ in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI₂ in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI₂ content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI₂ analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI₂/IP system protects against atrial fibrosis and that PGI₂is a therapeutic target for treating AF. The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12.