Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026
[Melatonin alleviates cardiomyocyte necroptosis in diabetic mice by inhibiting the STING signaling pathway].
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Ma Dan, Cao Shuyuan, Jiang Yi, Peng Yuce, He An, Luo Minghao, Luo Suxin
Аннотация
OBJECTIVES: To investigate the protective effect of melatonin against diabetic cardiomyopathy (DCM) and whether melatonin regulates cardiomyocyte necroptosis and inflammatory response through the stimulator of interferon genes (STING) signaling pathway.
METHODS: C57 mouse models of DCM induced by streptozotocin (STZ) injection were given an intraperitoneal injection of saline or melatonin (n=6), and 24 h later blood and myocardial samples were collected from the mice for analysis. A cell model of DCM was established in HL-1 cells by high glucose treatment (33 mmol/L). Pathological changes in myocardial tissue of the mice were observed using HE staining. Immunofluorescence staining and Western blotting were used to detect the key necroptosis proteins, and the pro-inflammatory factors including IL-1β, IL-6, and TNF-α were detected with Western blotting and ELISA to evaluate cell death and inflammation. The expression levels of the proteins associated with STING pathway activation (P-IRF3 and P-P65) were detected using immunohistochemistry and Western blotting.
RESULTS: In the diabetic mice and cell models of DCM, the STING signaling pathway was activated with significantly increased protein expressions of STING and P-IRF3. The myocardial tissues of DCM mice showed increased inflammatory infiltration with upregulated serum and myocardial levels of IL-1β, IL-6, and TNF-α and increased levels of necroptosis-related proteins P-MLKL, P-RIPK1, and P-RIPK3. Treatment with melatonin significantly inhibited the activation of the STING signaling pathway and reduced the expression levels of inflammatory factors and necroptosis-related proteins, and the use of the STING agonist DMXAA significantly attenuated the protective effect of melatonin.
CONCLUSIONS: Melatonin effectively alleviates cardiomyocyte necroptosis and inflammatory response in DCM by inhibiting the STING signaling pathway.
METHODS: C57 mouse models of DCM induced by streptozotocin (STZ) injection were given an intraperitoneal injection of saline or melatonin (n=6), and 24 h later blood and myocardial samples were collected from the mice for analysis. A cell model of DCM was established in HL-1 cells by high glucose treatment (33 mmol/L). Pathological changes in myocardial tissue of the mice were observed using HE staining. Immunofluorescence staining and Western blotting were used to detect the key necroptosis proteins, and the pro-inflammatory factors including IL-1β, IL-6, and TNF-α were detected with Western blotting and ELISA to evaluate cell death and inflammation. The expression levels of the proteins associated with STING pathway activation (P-IRF3 and P-P65) were detected using immunohistochemistry and Western blotting.
RESULTS: In the diabetic mice and cell models of DCM, the STING signaling pathway was activated with significantly increased protein expressions of STING and P-IRF3. The myocardial tissues of DCM mice showed increased inflammatory infiltration with upregulated serum and myocardial levels of IL-1β, IL-6, and TNF-α and increased levels of necroptosis-related proteins P-MLKL, P-RIPK1, and P-RIPK3. Treatment with melatonin significantly inhibited the activation of the STING signaling pathway and reduced the expression levels of inflammatory factors and necroptosis-related proteins, and the use of the STING agonist DMXAA significantly attenuated the protective effect of melatonin.
CONCLUSIONS: Melatonin effectively alleviates cardiomyocyte necroptosis and inflammatory response in DCM by inhibiting the STING signaling pathway.