Background Prevention of diabetic heart myocardial ischemia-reperfusion (IR) injury (MIRI) is challenging. Propofol attenuates MIRI through its reactive oxygen species scavenging property at high doses, while its use at high doses causes hemodynamic instability. Salvianolic acid A (SAA) is a potent antioxidant that confers protection against MIRI. Both propofol and SAA affect metabolic profiles through regulating Adenosine 5'-monophosphate-activated protein kinase (AMPK). The aim of this study was to investigate the protective effects and underlying mechanisms of low doses of propofol combined with SAA against diabetic MIRI. Methods Diabetes was induced in mice by a high-fat diet followed by streptozotocin injection, and MIRI was induced by coronary artery occlusion and reperfusion. Mice were treated with propofol at 46 mg/kg/h without or with SAA at 10 mg/kg/h during IR. Cardiac origin H9c2 cells were exposed to high glucose (HG) and palmitic acid (PAL) for 24 h in the absence or presence of cluster of differentiation 36 (CD36) overexpression or AMPK gene knockdown, followed by hypoxia/reoxygenation (HR) for 6 and 12 h. Results Diabetes-exacerbated MIRI is evidenced as significant increases in post-ischemic infarction with reductions in phosphorylated (p)-AMPK and increases in CD36 and ferroptosis. Propofol moderately yet significantly attenuated all the abovementioned changes, while propofol plus SAA conferred superior protection against MIRI to that of propofol. In vitro, exposure of H9c2 cells under HG and PAL decreased cell viability and increased oxidative stress that was concomitant with increased levels of ferroptosis and a significant increase in CD36, while p-AMPK was significantly reduced. Co-administration of low concentrations of propofol and SAA at 12.5 μM in H9c2 cells significantly reduced oxidative stress, ferroptosis and CD36 expression, while increasing p-AMPK compared to the effects of propofol at 25 μM. Moreover, either CD36 overexpression or AMPK silence significantly exacerbated HR-induced cellular injuries and ferroptosis, and canceled propofol- and SAA-mediated protection. Notably, p-AMPK expression was downregulated after CD36 overexpression, while AMPK knockdown did not affect CD36 expression. Conclusions Combinational usage of propofol and SAA confers superior cellular protective effects to the use of high-dose propofol alone, and it does so through inhibiting HR-induced CD36 overexpression to upregulate p-AMPK.

中文翻译：

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丙泊酚和丹酚酸 A 通过调节 CD36/AMPK 通路协同减轻糖尿病小鼠的心脏缺血再灌注损伤。


背景 预防糖尿病心脏心肌缺血再灌注（IR）损伤（MIRI）具有挑战性。高剂量异丙酚通过其活性氧清除特性减弱 MIRI，而高剂量使用会导致血流动力学不稳定。丹酚酸 A (SAA) 是一种有效的抗氧化剂，可预防 MIRI。丙泊酚和 SAA 均通过调节腺苷 5'-单磷酸激活蛋白激酶 (AMPK) 影响代谢特征。本研究旨在探讨低剂量异丙酚联合SAA对糖尿病MIRI的保护作用及其机制。方法采用高脂饮食诱导小鼠糖尿病，注射链脲佐菌素，通过冠状动脉闭塞再灌注诱导MIRI。在 IR 期间，小鼠接受 46 mg/kg/h 的异丙酚治疗，不加 SAA 或加 SAA 10 mg/kg/h。在不存在或存在分化簇 36 (CD36) 过表达或 AMPK 基因敲低的情况下，将心脏来源的 H9c2 细胞暴露于高葡萄糖 (HG) 和棕榈酸 (PAL) 24 小时，然后缺氧/复氧 (HR) 6 小时。和12小时。结果 糖尿病恶化的 MIRI 表现为缺血后梗塞显着增加，磷酸化 (p)-AMPK 减少，CD36 和铁死亡增加。异丙酚适度但显着地减弱了所有上述变化，而异丙酚加 SAA 对 MIRI 的保护作用优于异丙酚。在体外，H9c2 细胞暴露于 HG 和 PAL 下，细胞活力降低，氧化应激增加，同时铁死亡水平增加，CD36 显着增加，而 p-AMPK 显着降低。 12 时联合给予低浓度异丙酚和 SAA。与 25 μM 异丙酚的作用相比，5 μM 异丙酚在 H9c2 细胞中显着降低氧化应激、铁死亡和 CD36 表达，同时增加 p-AMPK。此外，CD36 过表达或 AMPK 沉默都会显着加剧 HR 诱导的细胞损伤和铁死亡，并取消丙泊酚和 SAA 介导的保护。值得注意的是，CD36过表达后p-AMPK表达下调，而AMPK敲低并不影响CD36表达。结论 丙泊酚和SAA联合使用比单独使用大剂量丙泊酚具有更好的细胞保护作用，其作用是通过抑制HR诱导的CD36过表达来上调p-AMPK。