Burger Dylan E, Xiang Fu-Li, Hammoud Lamis, Jones Douglas L, Feng Qingping
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 5C1.
J Pharmacol Exp Ther. 2009 Jun;329(3):900-7. doi: 10.1124/jpet.109.150896. Epub 2009 Mar 23.
Erythropoietin (EPO) is a potent cardioprotective agent in models of myocardial ischemia and reperfusion (I/R). It has been suggested recently that EPO may also reduce ventricular arrhythmia after I/R. The present study investigated the role of neuronal nitric oxide synthase (nNOS) on the antiarrhythmic effects of EPO. EPO treatment increased nNOS expression in isolated neonatal mouse ventricular myocytes. Cotreatment with the phosphatidylinositol 3 (PI3)-kinase inhibitor, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], or treatment of cardiomyocytes infected with a dominant negative adenovirus targeted to Akt1 (ADV-dnAkt1) blocked the effects of EPO on nNOS expression, suggesting that EPO regulates nNOS expression via PI3-kinase and Akt. To examine the in vivo antiarrhythmic effects of EPO, wild-type (WT) and nNOS(-/-) mice were anesthetized and, after a baseline measurement, subjected to myocardial I/R to provoke ventricular arrhythmias. Pretreatment with EPO 24 h before ischemia increased nNOS expression and significantly reduced the number of premature ventricular contractions (PVCs) and the incidence of ventricular tachycardia (VT) in WT mice. In contrast, treatment with EPO had no effect on PVCs or the incidence of VT in nNOS(-/-) mice. Furthermore, EPO treatment after ischemia significantly reduced the threshold dose of cesium chloride (CsCl) to induce VT. We conclude that EPO via nNOS protects the heart from spontaneous and CsCl-induced ventricular arrhythmia during myocardial I/R.
促红细胞生成素（EPO）在心肌缺血再灌注（I/R）模型中是一种有效的心脏保护剂。最近有人提出，EPO也可能减少I/R后的室性心律失常。本研究调查了神经元型一氧化氮合酶（nNOS）在EPO抗心律失常作用中的作用。EPO处理增加了分离的新生小鼠心室肌细胞中nNOS的表达。用磷脂酰肌醇3（PI3）激酶抑制剂LY294002[2-(4-吗啉基)-8-苯基-1(4H)-苯并吡喃-4-酮盐酸盐]共同处理，或用靶向Akt1的显性负腺病毒（ADV-dnAkt1）感染心肌细胞进行处理，均阻断了EPO对nNOS表达的影响，提示EPO通过PI3激酶和Akt调节nNOS表达。为了研究EPO的体内抗心律失常作用，将野生型（WT）和nNOS基因敲除（nNOS(-/-)）小鼠麻醉，在基线测量后，进行心肌I/R以诱发室性心律失常。缺血前24小时用EPO预处理可增加nNOS表达，并显著减少WT小鼠的室性早搏（PVC）数量和室性心动过速（VT）发生率。相比之下，用EPO处理对nNOS(-/-)小鼠的PVC或VT发生率没有影响。此外，缺血后用EPO处理可显著降低诱导VT的氯化铯（CsCl）阈值剂量。我们得出结论，EPO通过nNOS在心肌I/R期间保护心脏免受自发性和CsCl诱导的室性心律失常。
