HIF1α/MIF/CD74 signaling mediated OSA-induced atrial fibrillation by promoting M1 macrophages polarization

Abstract

Abstract Obstructive sleep apnea (OSA) is known to contribute to the increased occurrence and recurrence of atrial fibrillation (AF). However, the mechanism of chronic OSA-induced AF remains unknown. We constructed a rat model of chronic OSA and found that chronic OSA altered the pathological phenotype of atrial myocardial tissues, rendering it more susceptible to AF. Furthermore, we observed that chronic OSA promoted the polarization of M1 macrophages in the atrial tissue of rats, and the AF susceptibility induced by chronic OSA was reversed upon clearance of macrophages. Then, we found that macrophages induced an atrial fibrillation-like phenotype in atrial myocytes, while atrial myocytes promoted M1 polarization of macrophages, under hypoxia/reoxygenation treatment in vitro. Moreover, hypoxia/reoxygenation upregulated the expression of hypoxia-inducible factor 1-alpha (HIF1α) in atrial myocytes, which subsequently stimulated the transcription and expression of macrophage migration inhibitory factor (MIF) by binding to the promoter region of the MIF gene. The increased expression of MIF in atrial myocytes further activated the expression of nuclear factor-kappa B (NF-κB) through interaction with the macrophage surface receptor CD74, ultimately leading to M1 macrophages polarization. In summary, chronic OSA activated M1 macrophage polarization through the HIF1α/MIF/CD74 signaling pathway, thereby mediating the increased susceptibility to AF. This study offers novel insights into early prevention strategies and potential therapeutic targets for OSA-induced AF.