Differential role of PI3K/Akt pathway in the infarct size limitation and antiarrhythmic protection in the rat heart
Differential role of PI3K/Akt pathway in the infarct size limitation and antiarrhythmic protection in the rat heart
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DOI：
10.1007/s11010-006-9335-z
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发表时间：
2007-03-01
影响因子：
4.3
通讯作者：
Kolar, Frantisek
中科院分区：
文献类型：
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作者：
Ravingerova, Tana;Matejikova, Jana;Kolar, Frantisek
通过重复短暂的缺血（缺氧）发作或心脏对各种应激（例如慢性缺氧）的适应，可以实现针对长期缺血性损伤的内源性心脏保护。磷脂酰肌醇 3-激酶 (PI3K)/Akt 的激活与抗凋亡作用有关，但尚不清楚它是否是整体心脏挽救（包括预防心肌梗塞和心律失常）所必需的。我们重点关注 PI3K/Akt 在长期适应慢性间歇性低压缺氧（IHH；8 小时/天，25-30 次暴露，体内大鼠）和急性缺血预处理（IP；Langendorff 灌注心脏）的实验环境中，PI3K/Akt 在抗梗塞保护中的潜在共同作用。此外，我们还探讨了 PI3K/Akt 在缺血性室性心律失常易感性中的作用。在含氧量正常的开胸大鼠中，在测试闭塞/再灌注 (I/R) 前 5 分钟给予 PI3K/Akt 抑制剂 LY294002（LY；0.3 mg/kg）不会影响标准化为危险区域 (AR) 大小的梗死面积 (IS)。在缺氧大鼠中，LY 部分减弱了 IHH 的 IS 限制作用（IS/AR 59.7 +/- 4.1% 对比未治疗大鼠的 51.8 +/- 4.4%；p > 0.05），并将 IS/AR 增加至正常氧大鼠的值（64.9 +/- 5.1%）。在离体心脏中，在 I/R 前 15 分钟应用 LY (5 μM)，完全消除了 IP 的抗梗塞保护作用（IS/AR 55.0 +/- 4.9% 对比未处理心脏中的 15.2 +/- 1.2% 和非预处理对照中的 42.0 +/- 5.5%；p < 0.05）。在未预处理的心脏中，PI3K/Akt 抑制不会改变 IS/AR，另一方面，它显着抑制心律失常。在经 LY 处理的离体心脏中，室性早搏总数和室性心动过速 (VT) 发生率分别从对照组的 518 +/- 71 和 100% 降低至 155 +/- 15 和 12.5%（p < 0.05）。此外，IP与LY的包围并不能逆转IP的抗心律失常作用。这些结果表明，PI3K/Akt 级联的激活在大鼠心脏的 IS 限制机制中发挥作用，但不参与抗心律失常保护机制。
Endogenous cardiac protection against prolonged ischemic insult can be achieved by repeated brief episodes of ischemia (hypoxia) or by cardiac adaptation to various stresses such as chronic hypoxia. Activation of phosphatidylinositol 3-kinase (PI3K)/Akt is involved in antiapoptotic effects, however, it is not clear whether it is required for overall heart salvage including protection against myocardial infarction and arrhythmias. We focussed on the potential common role of PI3K/Akt in anti-infarct protection, in the experimental settings of long-term adaptation to chronic intermittent hypobaric hypoxia (IHH; 8 h/day, 25-30 exposures, in vivo rats) and acute ischemic preconditioning (IP; Langendorff-perfused hearts). In addition, we explored the role of PI3K/Akt in susceptibility to ischemic ventricular arrhythmias. In normoxic open-chest rats, PI3K/Akt inhibitor LY294002 (LY; 0.3 mg/kg) given 5 min before test occlusion/reperfusion (I/R) did not affect infarct size (IS) normalized to the size of area at risk (AR). In hypoxic rats, LY partially attenuated IS-limiting effect of IHH (IS/AR 59.7 +/- 4.1% vs. 51.8 +/- 4.4% in the non-treated rats; p > 0.05) and increased IS/AR to its value in normoxic rats (64.9 +/- 5.1%). In the isolated hearts, LY (5 mu M) applied 15 min prior to I/R completely abolished anti-infarct protection by IP (IS/AR 55.0 +/- 4.9% vs. 15.2 +/- 1.2% in the non-treated hearts and 42.0 +/- 5.5% in the non-preconditioned controls; p < 0.05). In the non-preconditioned hearts, PI3K/Akt inhibition did not modify IS/AR, on the other hand, it markedly suppressed arrhythmias. In the LY-treated isolated hearts, the total number of ventricular premature beats and the incidence of ventricular tachycardia (VT) was reduced from 518 +/- 71 and 100% in the controls to 155 +/- 15 and 12.5%, respectively (p < 0.05). Moreover, bracketing of IP with LY did not reverse antiarrhythmic effect of IP. These results suggest that activation of PI3K/Akt cascade plays a role in the IS-limiting mechanism in the rat heart, however, it is not involved in the mechanisms of antiarrhythmic protection.