Diabetic cardiomyopathy (DCM) is a severe complication of type 1 diabetic (T1D) patients, manifested as combined diastolic and systolic dysfunction. DCM is associated with impaired calcium homeostasis secondary to decreased calcium-sensitive receptor (CaSR) expression. Spermine, a direct agonist of CaSR, was found deficient in cardiomyocytes of T1D rats. However, the role of spermine in DCM was unclear. Here, we examined the cardioprotective effect of exogenous spermine on DCM in streptozotocin (STZ) induced-T1D rats and high-glucose (HG)-incubated neonatal rat cardiomyocytes. Exogenous spermine significantly attenuated cardiac dysfunction in T1D rats, characterized by improved echocardiography, less fibrosis, reduced myocardial endoplasmic reticulum (ER) stress and oxidative stress, and increased expression of myocardial membrane CaSR. In cultured neonatal rat cardiomyocytes, exogenous spermine attenuated myocardial injury induced by HG treatment, demonstrated by restored cellular glucose uptake capacity, reduced expression of apoptotic markers, lowered level of oxidative stress, ER stress and unfolded protein response, and upregulated cell membrane CaSR. Mechanistically, the cardioprotective effect of spermine appeared dependent upon effective elimination of reactive oxygen species (ROS) and up-regulation of CaSR expression by suppressing the Nrf2-ROS-p53-MuRF1 axis. Taken together, these results suggest that exogenous spermine protects against DCM in vivo and in vitro, partially via suppressing ROS and p53-mediated downregulation of cell membrane CaSR.

糖尿病心肌病 (DCM) 是 1 型糖尿病 (T1D) 患者的严重并发症，表现为舒张和收缩功能障碍。DCM 与继发于钙敏感受体 (CaSR) 表达降低的钙稳态受损有关。精胺是一种 CaSR 的直接激动剂，被发现在 T1D 大鼠的心肌细胞中存在缺陷。然而，精胺在 DCM 中的作用尚不清楚。在这里，我们检测了外源性精胺对链脲佐菌素 (STZ) 诱导的 T1D 大鼠和高糖 (HG) 孵育的新生大鼠心肌细胞中 DCM 的心脏保护作用。外源性精胺可显着减轻 T1D 大鼠的心功能不全，其特点是改善超声心动图、减少纤维化、降低心肌内质网 (ER) 应激和氧化应激，以及增加心肌膜 CaSR 的表达。在培养的新生大鼠心肌细胞中，外源性精胺减轻了 HG 处理诱导的心肌损伤，表现为细胞葡萄糖摄取能力恢复、凋亡标志物表达降低、氧化应激、ER 应激和未折叠蛋白反应水平降低，以及细胞膜 CaSR 上调。从机制上讲，精胺的心脏保护作用似乎取决于有效消除活性氧 (ROS) 和通过抑制 Nrf2-ROS-p53-MuRF1 轴上调 CaSR 表达。总之，这些结果表明外源性精胺可以预防 DCM 降低氧化应激、ER 应激和未折叠蛋白反应的水平，并上调细胞膜 CaSR。从机制上讲，精胺的心脏保护作用似乎取决于有效消除活性氧 (ROS) 和通过抑制 Nrf2-ROS-p53-MuRF1 轴上调 CaSR 表达。总之，这些结果表明外源性精胺可以预防 DCM 降低氧化应激、ER 应激和未折叠蛋白反应的水平，并上调细胞膜 CaSR。从机制上讲，精胺的心脏保护作用似乎取决于有效消除活性氧 (ROS) 和通过抑制 Nrf2-ROS-p53-MuRF1 轴上调 CaSR 表达。总之，这些结果表明外源性精胺可以预防 DCM在体内和体外，部分通过抑制 ROS 和 p53 介导的细胞膜 CaSR 下调。