Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Department of Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt.
Life Sci. 2020 Sep 1;256:117887. doi: 10.1016/j.lfs.2020.117887. Epub 2020 Jun 1.
Vascular complications are a leading cause of morbidity and mortality among diabetic patients. This work aimed to investigate possible influences of dimethyl fumarate (DMF) on streptozotocin (STZ) diabetes-associated vascular complications in rats, exploring its potential to modulate ROS-TXNIP-NLRP3 inflammasome pathway. Two weeks after induction of diabetes (via a single injection of 50 mg/kg STZ, i.p.), diabetic rats were administered either DMF (25 mg/kg/day) or its vehicle for further eight weeks. Age-matched normal and DMF-administered non-diabetic rats served as controls. DMF treatment elicited a mild ameliorative effect on diabetic glycemia. DMF reduced serum TG and AGE levels and enhanced serum HDL-C concentrations in diabetic rats. Moreover, DMF significantly diminished aortic levels of ROS and MDA and restored aortic GSH, SOD and Nrf2 to near-normal levels in STZ rats. Aortic mRNA levels of TXNIP, NLRP3 and NF-κB p65 in diabetic rats were significantly reduced by DMF treatment. Serum and aortic protein levels of TXNIP and aortic contents of IL-1β, iNOS, NLRP3 and TGF-β1 were significantly lower in DMF-diabetic animals than non-treated diabetic rats. Furthermore, protein expression of TNF-α and caspase-3 in diabetic aortas was greatly attenuated by DMF administration. DMF enhanced eNOS mRNA and protein levels and increased bioavailable NO in diabetic aortas. Functionally, DMF attenuated contractile responses of diabetic aortic rings to KCl and phenylephrine and enhanced their relaxant responses to acetylcholine. DMF also mitigated diabetes-induced fibrous tissue proliferation in aortic tunica media. Collectively, these findings demonstrate that DMF offered vasculoprotective influences on diabetic aortas via attenuation of ROS-TXNIP-NLRP3 inflammasome pathway.
血管并发症是糖尿病患者发病率和死亡率的主要原因。本研究旨在探讨富马酸二甲酯（DMF）对链脲佐菌素（STZ）诱导的糖尿病相关血管并发症的可能影响，探索其调节活性氧（ROS）-硫氧还蛋白相互作用蛋白（TXNIP）-NLRP3 炎性体途径的潜力。糖尿病诱导（通过单次腹腔注射 50mg/kg STZ）2 周后，糖尿病大鼠给予 DMF（25mg/kg/天）或其载体进一步 8 周。年龄匹配的正常和 DMF 给药的非糖尿病大鼠作为对照。DMF 治疗对糖尿病大鼠的血糖有轻度改善作用。DMF 降低了糖尿病大鼠的血清甘油三酯（TG）和 AGE 水平，提高了血清高密度脂蛋白胆固醇（HDL-C）浓度。此外，DMF 显著降低了 STZ 大鼠主动脉 ROS 和 MDA 水平，并使主动脉 GSH、SOD 和 Nrf2 恢复到接近正常水平。DMF 治疗显著降低了糖尿病大鼠主动脉 TXNIP、NLRP3 和 NF-κB p65 的 mRNA 水平。DMF 糖尿病大鼠的血清和主动脉 TXNIP 蛋白水平以及主动脉 IL-1β、iNOS、NLRP3 和 TGF-β1 含量均明显低于未治疗的糖尿病大鼠。此外，DMF 给药可显著减轻糖尿病大鼠主动脉 TNF-α 和 caspase-3 的蛋白表达。DMF 增强了糖尿病大鼠主动脉 eNOS mRNA 和蛋白水平，并增加了主动脉中生物可利用的一氧化氮（NO）。功能上，DMF 可减弱糖尿病大鼠主动脉环对 KCl 和苯肾上腺素的收缩反应，并增强其对乙酰胆碱的舒张反应。DMF 还减轻了糖尿病引起的主动脉中膜纤维组织增生。总之，这些发现表明，DMF 通过抑制 ROS-TXNIP-NLRP3 炎性体途径对糖尿病主动脉提供了血管保护作用。
