[Melatonin alleviates cardiomyocyte necroptosis in diabetic mice by inhibiting the STING signaling pathway].

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.