on and enhance reactive oxygen species (ROS) production. Apelin enhances the phosphatidylinositol 3-kinase (PI3K)/AKT and AMPK/acetyl-CoA carboxylase (ACC) pathways, promotes the complete fatty acid oxidation in the heart, and reduces the release of ROS. In this study, we examined whether exogenous (Pyr1) apelin-13 could reverse bupivacaine-induced cardiotoxicity. METHODS: We used the bupivacaine-induced inhibition model in adult male Sprague Dawley (SD) rats (n = 48) and H9c2 cardiomyocyte cell cultures to explore the role of apelin-13 in the reversal of bupivacaine cardiotoxicity, and its possible mechanism of action. AMPKα, ACC, carnitine palmitoyl transferase (CPT), PI3K, AKT, superoxide dismutase 1 (SOD1), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47-phox) were quantified. Changes in mitochondrial ultrastructure were examined, and mitochondrial DNA, cell viability, ROS release, oxygen consumption rate (OCR) were determined. RESULTS: Apelin-13 reduced bupivacaine-induced mitochondrial DNA lesions in SD rats (P < .001), while increasing the expression of AMPKα (P = .007) and PI3K (P = .002). Furthermore, apelin-13 blocked bupivacaine-induced depolarization of the mitochondrial membrane potential (P = .019) and the bupivacaine-induced increases in ROS (P = .001). Also, the AMPK pathway was activated by bupivacaine as well as apelin-13 (P = .002) in H9c2 cardiomyocytes. Additionally, the reduction in the PI3K expression by bupivacaine was mitigated by apelin-13 in H9c2 cardiomyocytes (P = .001). While the aforementioned changes induced by bupivacaine were not abated by apelin-13 after pretreatment with AMPK inhibitor compound C; the bupivacaine-induced changes were still mitigated by apelin-13, even when pretreated with PI3K inhibitor-LY294002. CONCLUSIONS: Apelin-13 treatment reduced bupivacaine-induced oxidative stress, attenuated mitochondrial morphological changes and mitochondrial DNA damage, enhanced mitochondrial energy metabolism, and ultimately reversed bupivacaine-induced cardiotoxicity. Our results suggest a role for the AMPK in apelin-13 reversal of bupivacaine-induced cardiotoxicity....

中文翻译：

---

Apelin-13 通过单磷酸腺苷活化蛋白激酶途径逆转布比卡因诱导的心脏毒性

并增强活性氧 (ROS) 的产生。Apelin 增强磷脂酰肌醇 3-激酶 (PI3K)/AKT 和 AMPK/乙酰辅酶 A 羧化酶 (ACC) 通路，促进心脏中脂肪酸的完全氧化，并减少 ROS 的释放。在这项研究中，我们检查了外源性 (Pyr1) apelin-13 是否可以逆转布比卡因诱导的心脏毒性。方法：我们在成年雄性 Sprague Dawley (SD) 大鼠 (n = 48) 和 H9c2 心肌细胞培养物中使用布比卡因诱导的抑制模型来探索 apelin-13 在逆转布比卡因心脏毒性中的作用及其可能的作用机制. AMPKα、ACC、肉碱棕榈酰转移酶 (CPT)、PI3K、AKT、超氧化物歧化酶 1 (SOD1) 和烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶 (p47-phox) 被量化。检查线粒体超微结构的变化，并测定线粒体 DNA、细胞活力、ROS 释放、耗氧率 (OCR)。结果：Apelin-13 减少了 SD 大鼠中布比卡因诱导的线粒体 DNA 损伤 (P < .001)，同时增加了 AMPKα (P = .007) 和 PI3K (P = .002) 的表达。此外，apelin-13 阻断了布比卡因诱导的线粒体膜电位去极化 (P = .019) 和布比卡因诱导的 ROS 增加 (P = .001)。此外，H9c2 心肌细胞中的 AMPK 通路被布比卡因和 apelin-13 (P = .002) 激活。此外，在 H9c2 心肌细胞中，apelin-13 减轻了布比卡因对 PI3K 表达的降低（P = .001）。虽然在用 AMPK 抑制剂化合物 C 预处理后，apelin-13 并未减弱布比卡因引起的上述变化；即使用 PI3K 抑制剂-LY294002 预处理，apelin-13 仍能减轻布比卡因引起的变化。结论：Apelin-13 治疗减少了布比卡因诱导的氧化应激，减轻了线粒体形态变化和线粒体 DNA 损伤，增强了线粒体能量代谢，并最终逆转了布比卡因诱导的心脏毒性。我们的结果表明 AMPK 在 apelin-13 逆转布比卡因诱导的心脏毒性中的作用。减轻线粒体形态变化和线粒体 DNA 损伤，增强线粒体能量代谢，并最终逆转布比卡因诱导的心脏毒性。我们的结果表明 AMPK 在 apelin-13 逆转布比卡因诱导的心脏毒性中的作用。减轻线粒体形态变化和线粒体 DNA 损伤，增强线粒体能量代谢，并最终逆转布比卡因诱导的心脏毒性。我们的结果表明 AMPK 在 apelin-13 逆转布比卡因诱导的心脏毒性中的作用。