昼夜节律增强剂诺比列汀逆转咪达唑仑对心肌缺血—再灌注损伤的有害影响

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昼夜节律增强剂诺比列汀逆转咪达唑仑对心肌缺血-再灌注损伤的有害影响

翻译：安丽  编辑：冯玉蓉  审校：曹莹

背景：近年来发现昼夜节律蛋白2（PER2）在心肌缺血中具有强大的心肌保护作用。基于围术期心肌梗死是最常见的主要心血管并发症，而且麻醉药可改变PER2的表达，我们假设，如果发生心肌缺血-再灌注（IR），麻醉药介导的PER2下调可能是有害的。

方法与结果：我们让小鼠暴露于戊巴比妥、芬太尼、氯胺酮、异丙酚、咪达唑仑或异氟烷，并测定心脏 Per2 mRNA水平。出乎意料，只有咪达唑仑导致 Per2 转录水平迅速显著下调。后续咪达唑仑预处理小鼠的研究采用原位小鼠心肌损伤模型，结果显示，与对照组相比，咪达唑仑处理组的梗死面积或肌钙蛋白-I血清水平显著增加。最近发现的类黄酮——诺比列汀，作为 PER2增强剂，完全消除了咪达唑仑在心肌IR损伤中的有害作用。此外，在野生型小鼠中，单独使用诺比列汀处理可显著降低心肌梗死面积或肌钙蛋白I水平，但在Per2−/−小鼠中则不能。对诺比列汀样黄酮类化合物药理学研究显示，诺比列汀和唐格列汀均能增强 PER2，在小鼠心肌缺血再灌注损伤模型中具有心肌保护作用。

结论：我们发现咪达唑仑介导的心脏PER2表达下调，是咪达唑仑预处理对心肌缺血-再灌注损伤中有害影响的潜在机制。这些结果强调PER2可作为一种心脏保护机制，并建议在经常使用咪达唑仑预处理的围术期心肌IR损伤中，PER2增强剂诺比列汀或唐格列汀可用于预防性治疗。

原始文献来源：Oyama Y, Bartman CM, Gile J, et al. The Circadian PER2 Enhancer Nobiletin Reverses the Deleterious Effects of Midazolam in Myocardial Ischemia and Reperfusion Injury.[J].Curr Pharm Des 2018,24(28).DOI：10.2174/1381612824666180924102530  

The circadian PER enhancer Nobiletin reverses the deleterious effects of midazolam in myocardial ischemia and reperfusion injury

Abstract

Background: Recently, we identified the circadian rhythm protein Period 2 (PER2) in robust cardioprotection from myocardial ischemia (MI). Based on findings that perioperative MI is the most common major cardiovascular complication and that anesthetics can alter the expression of PER2, we hypothesized that an anesthesia mediated downregulation of PER2 could be detrimental if myocardial ischemia and reperfusion (IR) would occur.

Methods and Results: We exposed mice to pentobarbital, fentanyl, ketamine, propofol, midazolam or isoflurane and determined cardiac Per2 mRNA levels. Unexpectedly, only midazolam treatment resulted in an immediate and significant downregulation of Per2 transcript levels. Subsequent studies in mice pretreated with midazolam using an in-situ mouse model for myocardial (IR)-injury revealed a significant and dramatic increase in infarct sizes or Troponin-I serum levels in the midazolam treated group when compared to controls. Using the recently identified flavonoid, nobiletin, as a PER2 enhancer completely abolished the deleterious effects of midazolam during myocardial IR-injury. Moreover, nobiletin treatment alone significantly reduced infarct sizes or Troponin I levels in wildtype but not in Per2 −/− mice. Pharmacological studies on nobiletin like flavonoids revealed that only nobiletin and tangeritin, both found to enhance PER2, were cardioprotective in our murine model for myocardial IR-injury.

Conclusion: We identified midazolam mediated downregulation of cardiac PER2 as an underlying mechanism for a deleterious effect of midazolam pretreatment in myocardial IR-injury. These findings highlight PER2 as a cardioprotective mechanism and suggest the PER2 enhancers nobiletin or tangeritin as preventative therapy for myocardial IR-injury in the perioperative setting where midazolam pretreatment occurs frequently.

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