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Mol. Life Sci."],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I\n                    <jats:sub>2<\/jats:sub>\n                    (PGI\n                    <jats:sub>2<\/jats:sub>\n                    ) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I\n                    <jats:sub>2<\/jats:sub>\n                    receptor (IP). However, the role of PGI\n                    <jats:sub>2<\/jats:sub>\n                    in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI\n                    <jats:sub>2<\/jats:sub>\n                    in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI\n                    <jats:sub>2<\/jats:sub>\n                    content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI\n                    <jats:sub>2<\/jats:sub>\n                    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\n                    <jats:italic>IP<\/jats:italic>\n                    -knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI\n                    <jats:sub>2<\/jats:sub>\n                    \/IP system protects against atrial fibrosis and that PGI\n                    <jats:sub>2<\/jats:sub>\n                    is a therapeutic target for treating AF.\n                  <\/jats:p>\n                  <jats:p>The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. 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