Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury
Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury
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DOI：
10.1016/j.yjmcc.2010.03.007
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发表时间：
2010-08-01
影响因子：
5
通讯作者：
Sato, Takayuki
中科院分区：
文献类型：
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作者：
Katare, Rajesh G.;Ando, Motonori;Sato, Takayuki
迷走神经刺激（VS）已被报道通过释放神经递质ACh来提高急性和慢性心肌梗死后的生存率。然而，其有益作用背后的确切机制尚不清楚。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。我们采用小鼠体内和体外模型研究了传出VS对心肌缺血损伤的影响。在体内，心肌缺血3小时后，VS显著增加了tnf - α在信使和蛋白水平的表达。在体外研究中，缺氧前乙酰胆碱治疗与未治疗的心肌细胞相比，诱导了tnf - α的显著上调。免疫荧光分析证实了体内和体外心肌细胞都能合成tnf - α。VS还显著降低心肌梗死面积（23.9 +/- 5.7% VS . 56 +/- 1.9%），激活细胞存活Akt级联系统。此外，ACh上调细胞存活TNFR2的表达，同时下调细胞破坏性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，其中VS介导的保护在体内和体外TNFR2（TNFR2(-/-)）和TNF受体双敲除(TNFR1（-/-)2(-/-)）小鼠中都失去了。VS和ACh通过差异调节TNF受体亚型保护心脏免受急性缺血或缺氧损伤。(C) 2010 Elsevier Ltd.版权所有。
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. (C) 2010 Elsevier Ltd. All rights reserved.