Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT
Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT
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DOI：
10.1152/ajpheart.00200.2015
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发表时间：
2015-08-15
影响因子：
4.8
通讯作者：
Janicki, Joseph S.
中科院分区：
文献类型：
--
作者：
Jubair, Shaiban;Li, Jianping;Janicki, Joseph S.
越来越多的证据表明，P物质在缺血再灌注后具有心脏保护作用，主要是由于其有效的冠状血管扩张作用。然而，在缺血后的腱细胞中观察到P物质的抗凋亡作用，其涉及AKT通路的激活。这表明P物质也可能通过直接激活心肌细胞中的AKT来提供心脏保护。本研究的目的是验证P物质通过激活细胞存活途径直接作用于心肌细胞来减弱缺血相关细胞死亡的假设。使用腹腔注射戊巴比妥钠（100 mg/kg）麻醉的7周龄雄性Sprague-Dawley大鼠。物质P防止细胞损伤的能力进行了评估缺血-再灌注后，在一个孤立的心脏制备和短期缺氧无再灌注使用左心室组织切片培养制备。此外，使用NK-1受体拮抗剂L732138和AKT抑制剂LY 294002评估NK-1受体和AKT参与。结果表明，P物质降低了两种制剂中乳酸脱氢酶的缺血相关释放以及缺氧左心室切片中的凋亡和坏死程度，表明其能够减轻细胞损伤;并诱导AKT磷酸化，AKT抑制剂和NK-1受体拮抗剂均阻止AKT磷酸化的增加，P物质能够减轻缺氧细胞损伤。结论P物质通过NK-1受体和AKT直接作用于心肌细胞，启动细胞存活途径，从而减少缺血/缺氧诱导的心肌细胞死亡。
Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT.