Maresin1 improves cardiac dysfunction via LGR6 in heatstroke

Heatstroke is a severe and life-threatening condition that can lead to cardiac dysfunction and poses a high risk of mortality. Maresin1, an endogenous lipid mediator, reportedly promotes inflammation resolution in various inflammatory diseases. However, its cardioprotective role during heatstroke has not been thoroughly investigated. In this study, we used ultra-performance liquid chromatography-tandem mass spectrometry to measure the levels of Maresin1 in the plasma and cardiac tissues of mice exposed to heatstroke. Our results indicated a notable decrease in Maresin1 levels under heatstroke conditions. In addition, the levels of leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6), a receptor for Maresin1, were increased in mice exposed to heatstroke. Exogenously administered Maresin1 significantly improved survival rates and alleviated the symptoms of heatstroke. Conversely, in Lgr6-knockout mice, the symptoms worsened, and the mortality rate increased. Transcriptomic analysis of the cardiac tissue and in vitro experiments have confirmed that Maresin1 exerts cardioprotective effects by inhibiting oxidative stress and promoting ATP synthesis through the upregulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) mediated via LGR6. Nuclear respiratory factor 1 (NRF1) and nuclear respiratory factor 2 (NRF2) were also increased downstream, likely as a secondary response associated with improved mitochondrial biogenesis rather than direct transcriptional regulation by LGR6. Our findings indicate that the Maresin1-LGR6 axis serves a cardioprotective role in heatstroke and is a potential therapeutic target for heatstroke-induced cardiac dysfunction.