The IL-27/IL-27R axis attenuates hypoxia-induced cardiac remodeling and is associated with altered p38 MAPK signaling

BACKGROUND: Chronic hypoxia is a major driver of pulmonary hypertension (PH) and adverse cardiac remodeling. Although IL-27/interleukin-27 receptor (IL-27R) signaling has been implicated in tissue-protective responses, its role in hypoxia-induced cardiac remodeling remains unclear. METHODS: We used a combination of in vivo and in vitro approaches to investigate the role of IL-27/IL-27R in hypoxia-induced cardiac remodeling. Wild-type (WT) and interleukin-27 receptor α knockout (IL-27Rα KO) mice were exposed to chronic hypoxia. Interventions included recombinant mouse IL-27 (rmIL-27), lipid nanoparticle-encapsulated IL-27 mRNA (LNP-IL-27 mRNA), and sildenafil. Echocardiographic, histological, and molecular analyses were performed to assess cardiac remodeling. RESULTS: IL-27Rα deficiency was associated with worsened hypoxia-induced remodeling, including more marked cardiac structural abnormalities, impaired functional indices, and increased myocardial fibrosis. rmIL-27 attenuated these changes and showed more consistent protective effects than LNP-IL-27 mRNA and sildenafil across the measured endpoints. In hypoxic cardiomyocytes, IL-27 was associated with altered downstream signaling, with p38 MAPK showing a pattern more closely associated with the protective phenotype than STAT1 or STAT3. CONCLUSION: The IL-27/IL-27R axis attenuates chronic hypoxia-induced cardiac remodeling, with associated changes in p38 MAPK signaling, although the underlying mechanisms require further investigation.