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

BACKGROUND: Obstructive sleep apnea (OSA) is known to contribute to the occurrence and recurrence of atrial fibrillation (AF). However, the mechanism remains unknown.

METHODS: Chronic OSA rat model was established to elucidate the role of macrophages in OSA-induced AF. Moreover, to reveal the mechanisms underlying the abnormal polarization of macrophages induced by chronic OSA, co-culture cell model of macrophages and atrial myocytes was created.

RESULTS: Chronic OSA altered the pathological phenotype of atrial myocardial tissues, rendering it more susceptible to AF. Furthermore, chronic OSA promoted the polarization of M1 macrophages in the atrial tissue, 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. Moreover, hypoxia/reoxygenation upregulated the expression of hypoxia-inducible factor 1-α (HIF1α) in atrial myocytes, which subsequently promoted the expression of macrophage migration inhibitory factor (MIF) by binding to the promoter region. The increased expression of MIF further activated the expression of nuclear factor-kappa B (NF-κB) through interaction with CD74, ultimately leading to M1 macrophages polarization.

CONCLUSIONS: Increased polarization of M1-type macrophages was involved in the increased susceptibility to AF induced by OSA. In mechanism, OSA increased MIF expression by HIF1α in atrial myocytes. Then, MIF activated NF-κB expression by CD74 in macrophages, consequently driving the polarization of M1-type macrophages. Finally, M1 macrophages exacerbated atrial remodeling through the secretion of inflammatory cytokines, which contributed to the increased susceptibility to AF.