Liu Shuai, Liu Fu-Zhong, Yan Jue-Yue, Fang Xing, Xu Zhi-Peng, Cai Hong-Liu, Yang Ying-Jun, Yu Yong-Wei
Department of Cardiology, The First People's Hospital of Jiashan, Jiaxing, Zhejiang, 314100, China; Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
Department of Cardiology, The First People's Hospital of Jiashan, Jiaxing, Zhejiang, 314100, China.
Free Radic Biol Med. 2024 Nov 1;224:405-417. doi: 10.1016/j.freeradbiomed.2024.09.003. Epub 2024 Sep 4.
Sepsis is a life-threatening severe inflammatory reaction caused by the host's dysregulated response to infection. Sepsis-induced myocardial dysfunction (SIMD) has been confirmed to occur in 50 % of patients with septic shock. Currently, the pathophysiological mechanism of SIMD is complex, and there is no targeted treatment. Elabela is another endogenous ligand of Aplnr (APJ). The protective effect of APJ on the heart has been proven. Elabela (Ela) has been shown to have a variety of cardiovascular protective effects. However, there are no studies demonstrating the protective effect of Ela-APJ axis on SIMD.
In vivo, C57BL/J mice were injected subcutaneously with 1 mg/kg/d Ela for 2 weeks, and in vitro, AC16 cells were treated with 1 μM Ela for 24 h. A 7-0 thread was used to ligate the distal end of the cecum, followed by puncture with a 20-gauge needle. Once a small amount of fluid leaks out, release the cecum back into the abdominal cavity. We measured the survival rates of the mice, performed ultrasound on their hearts, and evaluated the effects of the treatments. The serum and cell supernatant were extracted to detect myocardial injury markers and pyroptosis-related indicators. Western blotting was used to detect autophagy and pyroptosis-related protein. Molecular docking and other experiments were also used to detect changes in related proteins.
In vivo, Ela significantly improved the survival rate of septic mice, improved cardiac function, and reduced the production of myocardial injury markers, oxidative stress and pyroptosis. In vitro, Ela unblocked autophagy flow by affecting TFEB transcription. Autophagy reduces inflammation and oxidative stress by selectively degrading inflammatory bodies and ultimately alleviates pyroptosis.
We had demonstrated for the first time that in sepsis, Ela promoted the degradation of inflammasomes, reduced oxidative stress, and inhibited the occurrence of pyroptosis by unblocking autophagy flow.
脓毒症是由宿主对感染的失调反应引起的危及生命的严重炎症反应。脓毒症诱导的心肌功能障碍（SIMD）已被证实在50%的感染性休克患者中发生。目前，SIMD的病理生理机制复杂，且尚无针对性治疗方法。埃拉贝拉（Elabela）是血管紧张素Ⅱ1型受体相关蛋白（Aplnr，APJ）的另一种内源性配体。APJ对心脏的保护作用已得到证实。埃拉贝拉（Ela）已被证明具有多种心血管保护作用。然而，尚无研究证明Ela-APJ轴对SIMD的保护作用。
在体内实验中，将C57BL/J小鼠皮下注射1mg/kg/d的Ela，持续2周；在体外实验中，将AC16细胞用1μM的Ela处理24小时。用7-0丝线结扎盲肠远端，然后用20号针头穿刺。一旦有少量液体漏出，将盲肠放回腹腔。我们测量了小鼠的存活率，对其心脏进行超声检查，并评估治疗效果。提取血清和细胞上清液以检测心肌损伤标志物和焦亡相关指标。采用蛋白质免疫印迹法检测自噬和焦亡相关蛋白。还利用分子对接等实验检测相关蛋白的变化。
在体内实验中，Ela显著提高了脓毒症小鼠的存活率，改善了心脏功能，并减少了心肌损伤标志物的产生、氧化应激和焦亡。在体外实验中，Ela通过影响转录因子EB（TFEB）转录来解除自噬流阻滞。自噬通过选择性降解炎性小体来减少炎症和氧化应激，并最终减轻焦亡。
我们首次证明，在脓毒症中，Ela通过解除自噬流阻滞促进炎性小体降解，减少氧化应激，并抑制焦亡的发生。
