Diabetes‐induced endothelial dysfunction is critical for the development of diabetic cardiovascular complications. The aim of this study was to investigate the effect of niclosamide (Nic) on vascular endothelial dysfunction in streptozotocin (STZ)-induced diabetic rats. Male Sprague–Dawley rats were injected with a single intraperitoneal injection of STZ (75 mg/kg) to induce type 1 diabetes, and Nic (10 mg/kg) was intraperitoneally administered per day for 4 weeks. Endothelial function was evaluated as carbachol (CCh, an endothelium-dependent vasodilator)-evoked relaxation in the experiments performed on isolated thoracic aortas. The changes in the protein expressions of phosphorylated eNOS at serine 1177 (p-eNOS^Ser1177) and phosphorylated VASP at serine 239 (p-VASP^Ser239) of the rat aortas were analyzed by western blotting to determine whether NO/cGMP signaling is involved in the mechanism of Nic. STZ-injected rats had higher fasting blood glucose and less body weight compared to control rats (p < 0.05). Nic treatment did not affect blood glucose levels or body weights of the rats. CCh-induced endothelium-dependent relaxation of the aortic rings was significantly decreased in diabetic rats compared to control (E_max = 66.79 ± 7.41% and 90.28 ± 5.55%, respectively; p < 0.05). CCh-induced relaxation response was greater in Nic-treated diabetic rats compared to diabetic rats (E_max = 91.56 ± 1.20% and 66.79 ± 7.41%, respectively; p < 0.05). Phosphorylation of eNOS and VASP in aortic tissues was significantly reduced in diabetic rats, which were markedly increased by Nic treatment (p < 0.05). We demonstrated that Nic improved endothelial dysfunction possibly through the activation of NO/cGMP signaling without affecting hyperglycemia in diabetic rats. Our results suggesting that Nic has potential of repurposing for diabetic cardiovascular complications.

糖尿病引起的内皮功能障碍对糖尿病心血管并发症的发生至关重要。本研究的目的是研究氯硝柳胺 (Nic) 对链脲佐菌素 (STZ) 诱导的糖尿病大鼠血管内皮功能障碍的影响。雄性 Sprague-Dawley 大鼠腹腔注射单次 STZ（75 mg/kg）以诱导 1 型糖尿病，每天腹腔注射 Nic（10 mg/kg），持续 4 周。在对孤立的胸主动脉进行的实验中，内皮功能被评估为卡巴胆碱（CCh，一种内皮依赖性血管扩张剂）诱发的松弛。1177 位丝氨酸磷酸化 eNOS (p-eNOS ^Ser1177 ) 和 239 位丝氨酸磷酸化 VASP (p-VASP ^{Ser239 ) 蛋白表达的变化}) 通过蛋白质印迹分析大鼠主动脉以确定 NO/cGMP 信号传导是否参与 Nic 的机制。与对照组相比，注射 STZ 的大鼠空腹血糖较高，体重较轻（p  < 0.05）。Nic 治疗不影响大鼠的血糖水平或体重。与对照组相比，糖尿病大鼠中 CCh 诱导的主动脉环内皮依赖性舒张显着降低（E _max  = 66.79 ± 7.41% 和 90.28 ± 5.55%；p  < 0.05）。与糖尿病大鼠相比，经 Nic 治疗的糖尿病大鼠的 CCh 诱导的松弛反应更大（E _max  = 91.56 ± 1.20% 和 66.79 ± 7.41%；p < 0.05)。糖尿病大鼠主动脉组织中 eNOS 和 VASP 的磷酸化水平显着降低，而 Nic 治疗显着增加（p  < 0.05）。我们证明 Nic 可能通过激活 NO/cGMP 信号传导改善内皮功能障碍，而不影响糖尿病大鼠的高血糖。我们的结果表明，Nic 具有重新用于糖尿病心血管并发症的潜力。