Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect
Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect
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DOI：
10.1016/j.jtcvs.2008.08.020
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发表时间：
2009-01-01
影响因子：
6
通讯作者：
Sato, Takayuki
中科院分区：
文献类型：
--
作者：
Katare, Rajesh G.;Ando, Motonori;Sato, Takayuki
背景：尽管最近冠状动脉介入治疗取得了进展，但再灌注损伤仍然被认为是外科手术（如旁路移植术）患者的主要问题。在这里，我们展示了一种针对缺血再灌注损伤的新治疗策略：迷走神经介导的预防再灌注诱导的线粒体通透性过渡孔打开。方法：采用离体和离体大鼠模型研究迷走神经传出刺激对心肌再灌注损伤的影响。在离体模型中，心脏灌注了完整的迷走神经支配，这使我们能够研究迷走神经对心脏的影响，而没有其他全身影响。结果:与假刺激相比，迷走神经刺激在30分钟的全脑缺血后发挥了显著的抗梗死作用（心率为300次/分钟时，34% +/- 6% vs 85% +/- 9%；心率为250次/分钟时，37% +/- 4% vs 43% +/- 5%；心率为350次/分钟时，39% +/- 4% vs 88% +/- 7%），激活细胞存活Akt级联，阻止抗凋亡蛋白Bcl-2的下调。抑制细胞色素c的释放和caspase-3的激活。此外，迷走神经刺激治疗的心脏表现出左心室发展压的显著改善（78 +/- 5 vs 45 +/- 8 mm Hg），再灌注期间左心室舒张末期压的增量变化显著减弱。这些迷走神经刺激的有益作用被一种渗透性过渡开孔剂白术苷所消除。在原代培养心肌细胞的体外研究中，乙酰胆碱通过抑制通透性过渡孔打开来阻止再氧化诱导的线粒体跨膜电位崩溃。结论：迷走神经刺激可作为缺血心肌再灌注损伤的一种潜在的辅助治疗方法，其保护作用独立于其缓心作用。
Background: In spite of recent advances in coronary interventional therapy, reperfusion injury is still considered to be a major problem in patients undergoing surgical procedures, such as bypass grafting. Here we demonstrate a novel therapeutic strategy against ischemia-reperfusion injury: vagally mediated prevention of reperfusion-induced opening of mitochondrial permeability transition pore.Methods: We investigated the effects of efferent vagal stimulation on myocardial reperfusion injury with ex vivo and in vitro rat models. In the ex vivo model the hearts were perfused with intact vagal innervation, which allowed us to study the effects of the vagal nerve on the heart without other systemic effects.Results: Compared with sham stimulation, vagal stimulation exerted a marked anti-infarct effect irrespective of the heart rate (34% +/- 6% vs 85% +/- 9% at a heart rate of 300 beats/min, 37% +/- 4% vs 43% +/- 5% at a heart rate of 250 beats/min, and 39% +/- 4% vs 88% +/- 7% at a heart rate of 350 beats/min) after a 30-minute period of global ischemia, activated cell-survival Akt cascade, prevented downregulation of the antiapoptotic protein Bcl-2, and suppressed cytochrome-c release and caspase-3 activation. Furthermore, vagal stimulation-treated hearts exhibited a significant improvement in left ventricular developed pressure (78 +/- 5 vs 45 +/- 8 mm Hg) and a significant attenuation in an incremental change in left ventricular end-diastolic pressure during reperfusion. These beneficial effects of vagal stimulation were abolished by a permeability transition pore opener, atractyloside. In the in vitro study with primary-cultured cardiomyocytes, acetylcholine prevented a reoxygenation-induced collapse in mitochondrial transmembrane potential through inhibition of permeability transition pore opening.Conclusion: Vagal stimulation would be a potential adjuvant therapy for the rescue of ischemic myocardium from reperfusion injury, and the protective effects are independent of its bradycardiac effects.