Nociceptive-induced myocardial remote conditioning is mediated by neuronal gamma protein kinase C.
Nociceptive-induced myocardial remote conditioning is mediated by neuronal gamma protein kinase C.
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DOI：
10.1007/s00395-013-0381-x
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发表时间：
2013-09
影响因子：
9.5
通讯作者：
Gross GJ
中科院分区：
文献类型：
--
作者：
Gross ER;Hsu AK;Urban TJ;Mochly-Rosen D;Gross GJ
破译远程条件反射的分子机制可能为开发能够拓宽临床应用的治疗方法提供靶点。为了进一步研究这一点，我们检测了两种蛋白激酶C同工酶，即普遍表达的γ-PKC（εPKC）和神经元特异性γ-PKC（γPKC），是否介导伤害性诱导的远程心肌条件化。雄性Sprague-Dawley大鼠用于体内和离体心肌缺血-再灌注方案。在体内研究中，使用腹部手术切口进行比较，仅在腹部应用缓激肽或εPKC激活剂（εRACK）可减少心肌梗死面积（分别为45± 1%，44± 2%，切口：43± 2%，对照：63 ± 2%，P < 0.001）。Western blot结果显示心肌中只有εPKC高表达，而γPKC无表达。然而，将选择性γPKC抑制剂（γV5-3）应用于腹部皮肤阻断了这些策略中的任何一种的远程保护。使用无完整神经系统的离体心脏模型，与选择性经典PKC同工酶激活剂（激活α、β、βII和γ）不同，仅选择性εPKC激活可减轻心肌损伤。重要的是，在心肌缺血期间，在体内腹部给予经典的PKC同工酶激活剂（具有完整的神经系统，包括γPKC）与腹部切口或RACK一样有效地减少了梗死面积（分别为45±1% vs 45±2%和47± 1%）。经典的PKC激活剂诱导的保护作用也被脊髓手术横断阻断。这些发现确定了潜在的远程条件模拟，这些策略有效，即使在心肌缺血。还发现了一种涉及γPKC的伤害性诱导的远程条件反射的新机制。
Deciphering the remote conditioning molecular mechanism may provide targets to develop therapeutics that can broaden the clinical application. To further investigate this, we tested whether two protein kinase C isozymes, the ubiquitously expressed epsilon PKC (εPKC) and the neuronal specific gamma PKC (γPKC), mediate nociceptive-induced remote myocardial conditioning. Male Sprague-Dawley rats were used for both in vivo and ex vivo myocardial ischemia-reperfusion protocols. For the in vivo studies, using a surgical abdominal incision for comparison, applying only to the abdomen either bradykinin or the εPKC activator (ψεRACK) reduced myocardial infarct size (45±1%, 44±2%, respectively, versus incision: 43±2%, and control: 63±2%, P < 0.001). Western blot showed only εPKC, and not γPKC, is highly expressed in the myocardium. However, applying a selective γPKC inhibitor (γV5-3) to the abdominal skin blocked remote protection by any of these strategies. Using an ex vivo isolated heart model without an intact nervous system, only selective εPKC activation, unlike a selective classical PKC isozyme activator (activating α, β, βII and γ), reduced myocardial injury. Importantly, the classical PKC isozyme activator given to the abdomen in vivo (with an intact nervous system including γPKC) during myocardial ischemia reduced infarct size as effectively as an abdominal incision or ψεRACK (45±1% versus 45±2% and 47±1%, respectively). The classical PKC activator-induced protection was also blocked by spinal cord surgical transection. These findings identified potential remote conditioning mimetics, with these strategies effective even during myocardial ischemia. A novel mechanism of nociceptive-induced remote conditioning, involving γPKC, was also identified.
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影响因子：
9.5
作者：
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通讯作者：
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影响因子：
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