Department of Anesthesiology and Critical Care and Pain Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Department of Biochemistry and Molecular Biology Hebrew University of Jerusalem, Jerusalem, Israel.
PLoS One. 2019 Jan 25;14(1):e0211238. doi: 10.1371/journal.pone.0211238. eCollection 2019.
Sevoflurane postconditioning (sevo postC) is an attractive and amenable approach that can protect the myocardium against ischemia/reperfusion (I/R)-injury. Unlike ischemic preconditioning (IPC), sevo postC does not require additional induced ischemic periods to a heart that is already at risk. IPC was previously shown to generate myocardial protection against I/R-injury through regulation of iron homeostasis and de novo ferritin synthesis, a process found to be impaired in the diabetic state. The current study investigated whether alterations in iron homeostasis and ferritin mRNA and protein accumulation are also involved in the cardioprotective effects generated by sevo postC. It was also investigated whether the protective effects of sevo postC in the diabetic state can be salvaged by simvastatin, through inducing nitric oxide (NO) bioavailability/activity, in isolated streptozotocin (STZ)-induced diabetic hearts (DH). Isolated rat hearts from healthy Controls and diabetic animals were retrogradely perfused using the Langendorff configuration and subjected to prolonged ischemia and reperfusion, with and without (2.4 and 3.6%) sevo postC and/or pre-treatment with simvastatin (0.5 mg/kg). Sevo postC significantly reduced infarct size and improved myocardial function in healthy Controls but not in isolated DH. The sevo postC mediated myocardial protection against I/R-injury was not associated with de novo ferrtin synthesis. Furthermore, simvastatin aggravated myocardial injury after sevo postC in STZ-induced DHs, likely due to increasing NO levels. Despite the known mechanistic overlaps between PC and postC stimuli, distinct differences underlie the cardioprotective interventions against myocardial I/R-injury and are impaired in the DH. Sevo postC mediated cardioprotection, unlike IPC, does not involve de novo ferritin accumulation and cannot be rescued by simvastatin in STZ-induced DHs.
七氟醚后处理（sevo postC）是一种有吸引力且可行的方法，可保护心肌免受缺血/再灌注（I/R）损伤。与缺血预处理（IPC）不同，sevo postC 不需要对已经处于危险中的心脏进行额外的诱导性缺血期。IPC 先前被证明通过调节铁稳态和新合成的铁蛋白来产生心肌对 I/R 损伤的保护作用，而这一过程在糖尿病状态下被发现受损。本研究旨在探讨铁稳态和铁蛋白 mRNA 和蛋白积累的改变是否也参与了 sevo postC 产生的心脏保护作用。还研究了在糖尿病状态下，通过诱导一氧化氮（NO）生物利用度/活性，simvastatin 是否可以挽救 sevo postC 的保护作用，即在分离的链脲佐菌素（STZ）诱导的糖尿病心脏（DH）中。来自健康对照和糖尿病动物的分离大鼠心脏使用 Langendorff 构型逆行灌注，并进行长时间缺血和再灌注，有和没有（2.4 和 3.6%）sevo postC 和/或 simvastatin（0.5mg/kg）预处理。sevo postC 显著减少了健康对照大鼠的梗死面积并改善了心肌功能，但在分离的 DH 中则不然。sevo postC 介导的对 I/R 损伤的心肌保护作用与新合成的铁蛋白无关。此外，simvastatin 在 STZ 诱导的 DH 中加重了 sevo postC 后的心肌损伤，这可能是由于 NO 水平升高所致。尽管 PC 和 postC 刺激之间存在已知的机制重叠，但对心肌 I/R 损伤的心脏保护干预措施之间存在明显差异，并且在 DH 中受损。与 IPC 不同，sevo postC 介导的心脏保护作用不涉及新合成的铁蛋白积累，并且在 STZ 诱导的 DH 中不能被 simvastatin 挽救。
