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

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I-2 (PGI(2)) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I-2 receptor (IP). However, the role of PGI(2) in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI(2) in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI(2) content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI(2) 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 PGI(2)/IP system protects against atrial fibrosis and that PGI(2) is a therapeutic target for treating AF.