新型纳米再复苏液（TPP-MR）通过抑制铁死亡减轻失血性休克大鼠的心肌损伤。
The New Nano-Resuscitation Solution (TPP-MR) Attenuated Myocardial Injury in Hemorrhagic Shock Rats by Inhibiting Ferroptosis.
机构信息
Department of Anesthesiology, Daping Hospital, Army Medical University, Chongqing, 400042, People's Republic of China.
State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Daping Hospital, Army Medical University, Chongqing, 400042, People's Republic of China.
出版信息
Int J Nanomedicine. 2024 Jul 25;19:7567-7583. doi: 10.2147/IJN.S463121. eCollection 2024.
BACKGROUND
Hemorrhagic shock was a leading cause of death worldwide, with myocardial injury being a primary affected organ. As commonly used solutions in fluid resuscitation, acetated Ringer's (AR) and Lactate Ringer's solution (LR) were far from perfect for their adverse reactions such as lactic acidosis and electrolyte imbalances. In previous studies, TPP@PAMAM-MR (TPP-MR), a novel nanocrystal resuscitation fluid has been found to protect against myocardial injury in septic rats. However, its role in myocardial injury in rats with hemorrhagic shock and underlying mechanism is unclear.
METHODS
The hemorrhagic shock rats and hypoxia-treated cardiomyocytes (H9C2) were utilized to investigate the impact of TPP-MR on cardiac function, mitochondrial function, and lipid peroxidation. The expressions of ferritin-related proteins glutathione peroxidase 4 (GPX4), Acyl CoA Synthase Long Chain Family Member 4 (ACSL4), and Cyclooxygenase-2(COX2) were analyzed through Western blotting to explore the mechanism of TPP-MR on hemorrhagic myocardial injury.
RESULTS
TPP-MR, a novel nanocrystalline resuscitation fluid, was synthesized using TPP@PAMAM@MA as a substitute for L-malic acid. We found that TPP-MR resuscitation significantly reduced myocardial injury reflected by enhancing cardiac output, elevating mean arterial pressure (MAP), and improving perfusion. Moreover, TPP-MR substantially prolonged hemorrhagic shock rats' survival time and survival rate. Further investigations indicated that TPP-MR improved the mitochondrial function of myocardial cells, mitigated the production of oxidative stress agents (ROS) and increased the glutathione (GSH) content. Additionally, TPP-MR inhibited the expression of the ferroptosis-associated GPX4 protein, ACSL4 and COX2, thereby enhancing the antioxidant capacity.
CONCLUSION
The results showed that TPP-MR had a protective effect on myocardial injury in rats with hemorrhagic shock, and its mechanism might be related to improving the mitochondrial function of myocardial cells and inhibiting the process of ferroptosis.
背景
出血性休克是全球范围内主要的死亡原因，心肌损伤是主要受影响的器官。作为液体复苏中常用的溶液，醋酸林格氏液（AR）和乳酸林格氏液（LR）并不完美，它们会引起乳酸酸中毒和电解质失衡等不良反应。在之前的研究中，TPP@PAMAM-MR（TPP-MR），一种新型纳米晶体复苏液，已被发现可防止脓毒症大鼠的心肌损伤。然而，其在出血性休克大鼠心肌损伤中的作用及其潜在机制尚不清楚。
方法
利用出血性休克大鼠和缺氧处理的心肌细胞（H9C2），研究 TPP-MR 对心脏功能、线粒体功能和脂质过氧化的影响。通过 Western blot 分析铁蛋白相关蛋白谷胱甘肽过氧化物酶 4（GPX4）、酰基辅酶 A 合成酶长链家族成员 4（ACSL4）和环氧化酶 2（COX2）的表达，探讨 TPP-MR 对出血性心肌损伤的作用机制。
结果
TPP-MR，一种新型纳米晶体复苏液，用 TPP@PAMAM@MA 代替 L-苹果酸合成。我们发现 TPP-MR 复苏显著减轻了心肌损伤，表现为心输出量增加、平均动脉压（MAP）升高和灌注改善。此外，TPP-MR 显著延长了出血性休克大鼠的存活时间和存活率。进一步研究表明，TPP-MR 改善了心肌细胞的线粒体功能，减轻了氧化应激剂（ROS）的产生，并增加了谷胱甘肽（GSH）的含量。此外，TPP-MR 抑制了铁死亡相关的 GPX4 蛋白、ACSL4 和 COX2 的表达，从而增强了抗氧化能力。
结论
结果表明，TPP-MR 对出血性休克大鼠心肌损伤具有保护作用，其机制可能与改善心肌细胞线粒体功能和抑制铁死亡过程有关。
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