Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, 710004 Xi'an, Shaanxi, China.
Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, 710061 Xi'an, Shaanxi, China.
Front Biosci (Landmark Ed). 2024 Jul 26;29(7):274. doi: 10.31083/j.fbl2907274.
Diabetic cardiomyopathy (DCM) is an important cause of heart failure in diabetic patients. The aim of this study was to investigate the pathogenesis of DCM and to identify potential therapeutic targets.
A mouse model of type 1 DCM was constructed by continuous intraperitoneal injection of streptozotocin (STZ). Systolic and diastolic functions were measured by ultrasound. The expression of La-related protein 7 (LARP7), the stimulator of interferon genes (STING) pathway and light chain 3 (LC3) in myocardial tissue was detected by Western blot and immunofluorescence analyses. Neonatal mouse ventricular cardiomyocytes (NMVCMs) were isolated and cultured. An type 1 diabetes mellitus (T1DM) model was established by treatment with high glucose. Knockdown/overexpression of LARP7 and STING was achieved by adenovirus transduction, C-176 (a potent covalent inhibitor of STING), and plasmid transfection. The expression, activation, and localization of STING and LARP7 in cardiomyocytes was evaluated, as well as the interaction between the two. The effect of this interaction on the STING-dependent autophagy‒lysosomal pathway was also explored. In addition, the fibrosis and apoptosis of cardiomyocytes were evaluated.
High glucose was found to increase the expression and activation of STING and LARP7 in mouse myocardial tissue. This was accompanied by myocardial fibrosis, impaired autophagy degradation function and impaired cardiac function. These findings were further confirmed by experiments. High glucose caused LARP7 to translocate from the nucleus to the cytoplasm, where it interacted with accumulated STING to inhibit its degradation. Inhibition of STING or LARP7 expression significantly improved myocardial injury induced by high glucose.
Targeted inhibition of LARP7 or STING expression may be a potential therapeutic strategy for the treatment of DCM.
糖尿病心肌病（DCM）是糖尿病患者心力衰竭的重要原因。本研究旨在探讨 DCM 的发病机制，并确定潜在的治疗靶点。
通过连续腹腔注射链脲佐菌素（STZ）构建 1 型糖尿病心肌病小鼠模型。通过超声测量收缩和舒张功能。通过 Western blot 和免疫荧光分析检测心肌组织中 La 相关蛋白 7（LARP7）、干扰素基因刺激物（STING）通路和轻链 3（LC3）的表达。分离和培养新生小鼠心室心肌细胞（NMVCM）。用高葡萄糖处理建立 1 型糖尿病（T1DM）模型。通过腺病毒转导、C-176（一种有效的 STING 共价抑制剂）和质粒转染实现 LARP7 和 STING 的敲低/过表达。评估心肌细胞中 STING 和 LARP7 的表达、激活和定位，以及两者之间的相互作用。还探讨了这种相互作用对 STING 依赖性自噬溶酶体途径的影响。此外，评估了心肌细胞的纤维化和凋亡。
高葡萄糖被发现增加了小鼠心肌组织中 STING 和 LARP7 的表达和激活。这伴随着心肌纤维化、自噬降解功能受损和心功能受损。这些发现通过实验进一步得到证实。高葡萄糖导致 LARP7 从核转移到细胞质，在细胞质中与积累的 STING 相互作用，抑制其降解。抑制 STING 或 LARP7 表达显著改善了高葡萄糖引起的心肌损伤。
靶向抑制 LARP7 或 STING 表达可能是治疗 DCM 的潜在治疗策略。
