Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan.
J Mol Cell Cardiol. 2010 Aug;49(2):234-44. doi: 10.1016/j.yjmcc.2010.03.007. Epub 2010 Mar 17.
Vagal nerve stimulation (VS) has been reported to improve the survival after both acute and chronic myocardial infarction through the release of neurotransmitter ACh. However, the precise mechanism behind its beneficial effect is still unknown. In this study, we demonstrate the upregulation of tumor necrosis factor-alpha (TNF-alpha) and its cell survival TNF receptor-2 (TNFR2) as the mechanism behind VS induced myocardial protection. We investigated the effects of efferent VS on myocardial ischemic injury with in vivo and in vitro mouse models. In in vivo hearts VS significantly increased the expression of TNF-alpha both at the messenger and protein level after 3-hours of myocardial ischemia. In the in vitro studies ACh treatment before hypoxia, induced a significant upregulation of TNF-alpha compared to the untreated cardiomyocytes. Immunofluorescence analysis confirmed the synthesis of TNF-alpha by cardiomyocytes both in vivo and in vitro. VS also significantly reduced the myocardial infarct size (23.9+/-5.7% vs. 56+/-1.9%) and activated the cell survival Akt cascade system. Further, ACh upregulated the cell survival TNFR2 expression, while downregulating the cell destructive TNF receptor 1 (TNFR1) expression. These results were confirmed using the TNF receptors deficient mice, where the VS mediated protection was lost both in vivo and in vitro in TNFR2 (TNFR2(-/-)) and TNF receptors double knock out (TNFR1(-/-)2(-/-)) mice. VS and ACh protects the heart against acute ischemia or hypoxic injury by differentially regulating the TNF receptor subtypes.
迷走神经刺激（VS）已被报道通过释放神经递质 ACh 来改善急性和慢性心肌梗死后的存活率。然而，其有益效果的确切机制仍不清楚。在这项研究中，我们证明了肿瘤坏死因子-α（TNF-α）及其细胞存活 TNF 受体-2（TNFR2）的上调是 VS 诱导心肌保护的机制。我们用体内和体外小鼠模型研究了传出 VS 对心肌缺血损伤的影响。在体内心脏中，VS 在 3 小时心肌缺血后显著增加 TNF-α 的信使和蛋白水平的表达。在体外研究中，与未处理的心肌细胞相比，缺氧前用 ACh 处理诱导 TNF-α 的显著上调。免疫荧光分析证实了 TNF-α在体内和体外由心肌细胞合成。VS 还显著减少了心肌梗死面积（23.9+/-5.7% vs. 56+/-1.9%），并激活了细胞存活 Akt 级联系统。此外，ACh 上调了细胞存活 TNFR2 的表达，同时下调了细胞破坏性 TNF 受体 1（TNFR1）的表达。这些结果在 TNF 受体缺失小鼠中得到了证实，在体内和体外，VS 介导的保护在 TNFR2（TNFR2(-/-)）和 TNF 受体双敲除（TNFR1(-/-)2(-/-)）小鼠中均丢失。VS 和 ACh 通过差异调节 TNF 受体亚型来保护心脏免受急性缺血或缺氧损伤。
