This study examined the cardiac anti-cardiomyopathy (DC) protective effect of urolithin A in streptozotocin (STZ)-treated rats and investigated if this protection involves activation of SIRT1 signaling. Diabetes was induced first STZ (65 mg/kg, i.p.) before starting the experiments. Adult male rats (n = 8/group) were treated for 8 weeks as control (non-diabetic), control + urolithin A (2.5 mg/kg/i.p.), STZ, STZ + urolithin A, and STZ + urolithin A + Ex-527 (1 mg/kg/i.p.) (a SIRT1 inhibitor). With no effect on fasting glucose and insulin levels, urolithin A improved left ventricular (LV) function and structure and reduced heart weight and serum levels of cardiac markers in STZ-treated rats. Also, it prevented collagen deposition, reduced mRNA levels of Bax, cleaved caspaspe3, collagen 1A1, transforming growth factor-β1 (TGF-β1), and Smad3 but enhanced those of Bcl2 in the LVs of diabetic rats. However, urolithin A suppressed the generation of reactive oxygen species (ROS), activated the nuclear factor erythroid 2–related factor 2 (Nrf2), and increased the levels of manganese superoxide dismutase (MnSOD) and total glutathione (GSH) in the LVs of the non-diabetic and diabetic rats, In parallel, it suppressed the cardiac activity of NF-nuclear factor-kappa beta p65 (κB p65) and reduced levels of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Coincided with these events, urolithin A promoted higher activity, mRNA, and total/nuclear protein levels of SIRT1 and lowered the levels of acetyl-FOXO1, Nrf2, NF-κB, and p53. All these benefits of urolithin A were prevented by Ex-527. In conclusion, urolithin A protects against DC by activating SIRT signaling.

本研究检查了尿石素 A 在链脲佐菌素 (STZ) 治疗的大鼠中的心脏抗心肌病 (DC) 保护作用，并调查了这种保护是否涉及 SIRT1 信号传导的激活。在开始实验之前首先诱导糖尿病（65 mg/kg，ip）。成年雄性大鼠 (n = 8/组) 作为对照 (非糖尿病)、对照 + 尿石素 A (2.5 mg/kg/ip)、STZ、STZ + 尿石素 A 和 STZ + 尿石素 A + Ex 治疗 8 周-527 (1 mg/kg/ip)（一种 SIRT1 抑制剂）。尿石素 A 对空腹血糖和胰岛素水平没有影响，改善了 STZ 治疗大鼠的左心室 (LV) 功能和结构，并降低了心脏重量和血清心脏标志物水平。此外，它还可以防止胶原蛋白沉积，降低 Bax 的 mRNA 水平，切割 caspaspe3，胶原蛋白 1A1，转化生长因子-β1 (TGF-β1)，和 Smad3，但增强了糖尿病大鼠 LV 中 Bcl2 的水平。然而，尿石素 A 抑制了活性氧 (ROS) 的产生，激活了核因子红细胞 2 相关因子 2 (Nrf2)，并增加了 LV 中锰超氧化物歧化酶 (MnSOD) 和总谷胱甘肽 (GSH) 的水平。在非糖尿病和糖尿病大鼠中，它同时抑制 NF-核因子-kappa β p65 (κB p65) 的心脏活动，并降低肿瘤坏死因子-α (TNF-α) 和白细胞介素-6 (IL -6)。与这些事件同时发生，尿石素 A 促进了 SIRT1 更高的活性、mRNA 和总/核蛋白水平，并降低了乙酰 FOXO1、Nrf2、NF-κB 和 p53 的水平。Ex-527 阻止了尿石素 A 的所有这些好处。总之，尿石素 A 通过激活 SIRT 信号传导来防止 DC。