Department of Cardiac Surgery, Qingdao Fuwai Cardiovascular Hospital, Qingdao, China.
Department of Nursing, People's Hospital of Chiping, Chiping, China.
Shock. 2021 Sep 1;56(3):440-449. doi: 10.1097/SHK.0000000000001751.
Ferroptosis has been found to play an important role in myocardial ischemia reperfusion (MIR) injury (MIRI). This study aimed to explore whether the improvement effect of Etomidate (Eto) on MIRI was related to ferroptosis.
The MIRI rats were constructed using left anterior descending artery occlusion for 30 min followed by reperfusion for 3 h. The Eto post-conditioning was performed by Eto administration at the beginning of the reperfusion. For rescue experiments, MIRI rats were pretreated with ferroptosis inducer erastin or Nrf2 inhibitor ML385 intraperitoneally 1 h prior to MIR surgery.
Eto mitigated cardiac dysfunction and myocardium damage, as well as the release of creatine kinase and lactate dehydrogenase caused by ischemia/reperfusion (IR). Additionally, Eto reduced the expression of myocardial fibrosis-related proteins (collagen II and α-smooth muscle actin) and the secretion of inflammatory factors (IL-6, IL-1β, and TNF-α) in MIRI rats. Also, Eto inhibited IR-induced ferroptosis in myocardium, including reducing superoxide dismutase content, glutathione activity, and glutathione peroxidase 4 expression, while increasing the levels of malondialdehyde and iron and Acyl-CoA synthetase long-chain family member 4. Moreover, the inhibition of Eto on IR-induced myocardial fibrosis and inflammation could be eliminated by erastin. The up-regulation of Nrf2 and HO-1 protein expression, and the nuclear translocation of Nrf2 induced by Eto in the myocardial tissues of MIRI rats, could be prevented by erastin. Besides, ML385 eliminated the inhibition of Eto on ferroptosis induced by MIR.
Eto attenuated the myocardial injury by inhibiting IR-induced ferroptosis via Nrf2 pathway, which may provide a new idea for clinical reperfusion therapy.
铁死亡已被发现在心肌缺血再灌注（MIR）损伤（MIRI）中发挥重要作用。本研究旨在探讨依托咪酯（Eto）改善 MIRI 的作用是否与铁死亡有关。
采用左前降支结扎 30min 再灌注 3h 的方法构建 MIRI 大鼠模型。Eto 后处理在再灌注开始时给予 Eto 给药。对于抢救实验，MIRI 大鼠在 MIR 手术前 1h 经腹腔内给予铁死亡诱导剂 erastin 或 Nrf2 抑制剂 ML385 预处理。
Eto 减轻了由缺血/再灌注（IR）引起的心脏功能障碍和心肌损伤，以及肌酸激酶和乳酸脱氢酶的释放。此外，Eto 降低了 MIRI 大鼠心肌纤维化相关蛋白（胶原 II 和α-平滑肌肌动蛋白）和炎症因子（IL-6、IL-1β和 TNF-α）的表达。此外，Eto 抑制了 IR 诱导的心肌铁死亡，包括降低超氧化物歧化酶含量、谷胱甘肽活性和谷胱甘肽过氧化物酶 4 表达，同时增加丙二醛和铁水平以及酰基辅酶 A 合成酶长链家族成员 4 的水平。此外，Eto 对 IR 诱导的心肌纤维化和炎症的抑制作用可以被 erastin 消除。Eto 在 MIRI 大鼠心肌组织中诱导的 Nrf2 和 HO-1 蛋白表达上调以及 Nrf2 的核转位，可以被 erastin 阻断。此外，ML385 消除了 Eto 对 MIR 诱导的铁死亡的抑制作用。
Eto 通过 Nrf2 通路抑制 IR 诱导的铁死亡减轻心肌损伤，这可能为临床再灌注治疗提供新的思路。
