The role and mechanism of LARP7 in regulating the STING-dependent autophagy-lysosomal negative feedback loop in diabetic cardiomyopathy

Abstract

Abstract Background Diabetic cardiomyopathy (DCM) is an important cause of heart failure in diabetic patients, and there is no specific drug for DCM. The aim of this study was to investigate the pathogenesis of DCM and identify potential therapeutic targets. Methods Neonatal mouse ventricular cardiomyocytes (NMVCMs) were isolated and cultured. Type 1 diabetes mellitus (T1DM) models were established by high glucose (33 mmol/L) treatment. The knockdown/overexpression of LARP7 was achieved through adenovirus transduction, the overexpression of STING was achieved through plasmid transfection, and the inhibition of STING was achieved through C-176. Then, the expression, activation, and localization of STING and LARP7 in cardiomyocytes under different treatment conditions were observed, and the interaction between the two and the effect of this interaction on the STING-dependent autophagy‒lysosomal "negative feedback loop" were explored. In addition, the fibrosis and apoptosis of cardiomyocytes were evaluated. Results In this study, high glucose increased the expression and activation of STING in NMVCMs, which was accompanied by increased α-SMA and caspase3, and the degradation of STING through the autophagy-lysosomal pathway was suppressed. In addition, high glucose levels caused LARP7 to translocate from the nucleus to the cytoplasm and interact with accumulated STING to inhibit STING degradation, whereas inhibiting STING or LARP7 expression significantly improved high glucose-induced myocardial injury. Conclusion Under high glucose conditions, LARP7 damages mouse cardiomyocytes by inhibiting the STING-dependent autophagy-lysosomal degradation pathway. Targeted inhibition of LARP7 or STING expression may be a potential therapeutic strategy for the treatment of DCM.