Journal of molecular and cellular cardiology · 2026
Melatonin promotes coronary angiogenesis and ameliorates cardiac dysfunction after myocardial infarction via endothelial LRRC8A.
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Jie Lingjun, Zhou Tianli, Li Guiyang, Shen Wei, Chen Jiajin, Wu Penglong, Wu Jian, Zhang Yanhui
Аннотация
BACKGROUND: Accumulating evidence suggests that melatonin (MT) protects against myocardial infarction (MI), but its targets and molecular mechanisms remain largely unknown. This study aimed to uncover the endothelial targets and signaling pathways through which MT improves cardiac function in MI.
METHODS: An integrated strategy combining network pharmacology, molecular docking, in vitro endothelial cell assays, and endothelial-specific LRRC8A knockout mice was used to elucidate the role and mechanisms of MT in MI.
RESULTS: Network analysis identified angiogenesis-related signaling as a major target of MT. Molecular docking and electrophysiology revealed stable binding and functional activation of LRRC8A by MT. In vitro, low-dose MT promoted proliferation, migration, and tube formation via upregulating LRRC8A and activating the downstream AKT/eNOS/HIF1α signaling pathway; these effects were abolished by LRRC8A inhibition or knockdown. In vivo, MT improved cardiac systolic function and coronary angiogenesis in MI mice; however, these benefits were eliminated by endothelial-specific deletion of LRRC8A or the pharmacological blockade.
CONCLUSION: Our findings not only identify the LRRC8A as a novel endothelial target for MT's benefits in MI, but also pave the way for its development as a therapeutic agent for ischemic heart disease.
METHODS: An integrated strategy combining network pharmacology, molecular docking, in vitro endothelial cell assays, and endothelial-specific LRRC8A knockout mice was used to elucidate the role and mechanisms of MT in MI.
RESULTS: Network analysis identified angiogenesis-related signaling as a major target of MT. Molecular docking and electrophysiology revealed stable binding and functional activation of LRRC8A by MT. In vitro, low-dose MT promoted proliferation, migration, and tube formation via upregulating LRRC8A and activating the downstream AKT/eNOS/HIF1α signaling pathway; these effects were abolished by LRRC8A inhibition or knockdown. In vivo, MT improved cardiac systolic function and coronary angiogenesis in MI mice; however, these benefits were eliminated by endothelial-specific deletion of LRRC8A or the pharmacological blockade.
CONCLUSION: Our findings not only identify the LRRC8A as a novel endothelial target for MT's benefits in MI, but also pave the way for its development as a therapeutic agent for ischemic heart disease.