The Circadian PER2 Enhancer Nobiletin Reverses the Deleterious Effects of Midazolam in Myocardial Ischemia and Reperfusion Injury.
The Circadian PER2 Enhancer Nobiletin Reverses the Deleterious Effects of Midazolam in Myocardial Ischemia and Reperfusion Injury.
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DOI：
10.2174/1381612824666180924102530
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发表时间：
2018
影响因子：
3.1
通讯作者：
Eckle T
中科院分区：
文献类型：
--
作者：
Oyama Y;Bartman CM;Gile J;Sehrt D;Eckle T
最近，我们确定了昼夜节律蛋白周期2（PER 2）在强大的心肌缺血（MI）的心脏保护。基于围手术期MI是最常见的主要心血管并发症，麻醉剂可以改变PER 2的表达，我们假设如果发生心肌缺血和再灌注（IR），麻醉介导的PER 2下调可能是有害的。我们将小鼠暴露于戊巴比妥、芬太尼、氯胺酮、丙泊酚、咪达唑仑或异氟烷，并测定心脏Per 2 mRNA水平。出乎意料的是，只有咪达唑仑治疗导致Per 2转录水平的立即和显著下调。使用心肌（IR）损伤原位小鼠模型对咪达唑仑预处理小鼠进行的后续研究显示，与对照组相比，咪达唑仑治疗组的梗死面积或肌钙蛋白-I血清水平显著且急剧增加。使用最近鉴定的类黄酮，nobilopropyl，作为PER 2增强剂完全消除了心肌IR损伤过程中咪达唑仑的有害作用。此外，单独使用诺贝尔碱治疗可显著降低野生型小鼠的梗死面积或肌钙蛋白I水平，但在Per 2 −/−小鼠中则不然。对川陈皮类黄酮的药理学研究表明，只有川陈皮和橘子苷，都发现增强PER 2，在我们的小鼠模型心肌IR损伤的心脏保护。我们确定咪达唑仑介导的心脏PER 2下调是咪达唑仑预处理对心肌IR损伤有害作用的潜在机制。这些研究结果突出了PER 2作为一种心脏保护机制，并表明PER 2增强剂nobiltamine或tangeritin作为围手术期心肌IR损伤的预防性治疗，其中咪达唑仑预处理频繁发生。
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. 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. 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.