Cardioprotection by ε-protein kinase C activation from ischemia -: Continuous delivery and antiarrhythmic effect of an ε-protein kinase C-activating peptide
Cardioprotection by ε-protein kinase C activation from ischemia -: Continuous delivery and antiarrhythmic effect of an ε-protein kinase C-activating peptide
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DOI：
10.1161/01.cir.0000151614.22282.f1
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发表时间：
2005-01-04
期刊：
影响因子：
37.8
通讯作者：
Mochly-Rosen, D
中科院分区：
文献类型：
--
作者：
Inagaki, K;Begley, R;Mochly-Rosen, D
背景--我们以前发现，一种选择性的ε-蛋白激酶C（PKC）激活肽，psiepsilonRACK，在缺血事件发生前离体给药时，可对缺血-再灌注产生心脏保护作用。在这里，我们测试了是否在体内连续全身递送psiepsilonRACK赋予持续的心脏保护对缺血再灌注在离体小鼠心脏和psiepsilonRACK治疗是否减少梗死面积或致命的心律失常在猪heartsinvivo.Methods和结果-后psiepsilonRACK是急性或连续的小鼠全身给药，心脏进行缺血再灌注在一个孤立的灌注模型。而psiepsilonRACK诱导的心脏保护作用持续1小时后，单次腹腔注射，连续治疗与psiepsilonRACK诱导持续预处理状态在10天的交付。持续给予psiepsilonRACK后，治疗效果没有脱敏，epsilonPKC没有下调，也没有不良反应。使猪心在体内经受缺血-再灌注，并且在缺血的前10分钟期间通过冠状动脉内注射施用psiepsilonRACK。psiepsilonRACK治疗可减少梗死面积（34+/-2% vs 14+/-1%，对照vs psiepsilonRACK），并导致缺血再灌注期间室颤病例减少（87.5%对50%，对照对psiepsilonRACK）。结论-epsilonPKC激活剂psiepsilonRACK在体内和体外均诱导心脏保护，降低缺血-再灌注期间致死性心律失常的发生率，持续给药后未引起epsilonPKC的脱敏或下调。因此，psiepsilonRACK可能对缺血性心脏病患者有用。此外，psiepsilonRACK肽应该是一种有用的药理学试剂，用于动物研究，其中需要在体内系统和持续调节epsilonPKC。
Background - We previously showed that a selective activator peptide of epsilon-protein kinase C (PKC), psiepsilonRACK, conferred cardioprotection against ischemia-reperfusion when delivered ex vivo before the ischemic event. Here, we tested whether in vivo continuous systemic delivery of psiepsilonRACK confers sustained cardioprotection against ischemia-reperfusion in isolated mouse hearts and whether psiepsilonRACK treatment reduces infarct size or lethal arrhythmias in porcine hearts in vivo.Methods and Results - After psiepsilonRACK was systemically administered in mice either acutely or continuously, hearts were subjected to ischemia-reperfusion in an isolated perfused model. Whereas psiepsilonRACK-induced cardioprotection lasted 1 hour after a single intraperitoneal injection, continuous treatment with psiepsilonRACK induced a sustained preconditioned state during the 10 days of delivery. There was no desensitization to the therapeutic effect, no downregulation of epsilonPKC, and no adverse effects after sustained psiepsilonRACK delivery. Porcine hearts were subjected to ischemia-reperfusion in vivo, and psiepsilonRACK was administered by intracoronary injection during the first 10 minutes of ischemia. psiepsilonRACK treatment reduced infarct size (34+/-2% versus 14+/-1%, control versus psiepsilonRACK) and resulted in fewer cases of ventricular fibrillation during ischemia-reperfusion (87.5% versus 50%, control versus psiepsilonRACK).Conclusions - The epsilonPKCactivator psiepsilonRACK induced cardioprotection both in vivo and ex vivo, reduced the incidence of lethal arrhythmia during ischemia-reperfusion, and did not cause desensitization or downregulation of epsilonPKC after sustained delivery. Thus, psiepsilonRACK may be useful for patients with ischemic heart disease. In addition, the psiepsilonRACK peptide should be a useful pharmacological agent for animal studies in which systemic and sustained modulation of epsilonPKC in vivo is needed.