Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit
Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit
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DOI：
10.1152/ajpheart.00490.2007
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发表时间：
2007-10-01
影响因子：
4.8
通讯作者：
Sugimachi, Masaru
中科院分区：
文献类型：
--
作者：
Uemura, Kazunori;Li, Meihua;Sugimachi, Masaru
迷走神经刺激已被认为可以改善心力衰竭时的左心室（LV）重构。然而，迷走神经刺激是否以及在多大程度上影响心肌中的基质金属蛋白酶（MMP）和MMP的组织抑制剂（TIMP）尚不清楚，已知它们在LV重构中起关键作用。因此，我们研究了电刺激迷走神经对心肌缺血-再灌注（I/R）损伤模型中心肌MMPs和TIMPs表达和激活的影响。麻醉家兔行左冠状动脉阻断60 min，再灌注180 min（I/R-VS，n = 8）或不刺激迷走神经（I/R，n = 7）。未进行冠状动脉闭塞的兔（VS，n = 7）或未进行迷走神经刺激的兔（假手术，n = 7）用作对照。总MMP-9蛋白在I/R-VS和I/R中的左冠状动脉闭塞后显著增加，与VS和假手术值相比程度相似。I/R-VS组内源性活性MMP- 9蛋白水平明显低于I/R组。与I/R、VS和sham组相比，I/R-VS中TIMP-1 mRNA表达显著增加。I/R-VS组和VS组TIMP-1蛋白表达较I/R组和Sham组显著增加。心脏微透析技术表明，局部灌注乙酰胆碱增加透析液TIMP-1蛋白水平，这是由共同灌注阿托品抑制。免疫组化显示，TIMP-1蛋白在用于灌注乙酰胆碱的透析探针周围的心肌细胞中强烈表达。总之，在兔心肌I/R损伤模型中，迷走神经刺激诱导心肌细胞中TIMP- 1的表达并降低活性MMP-9。
Vagal nerve stimulation has been suggested to ameliorate left ventricular (LV) remodeling in heart failure. However, it is not known whether and to what degree vagal nerve stimulation affects matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) in myocardium, which are known to play crucial roles in LV remodeling. We therefore investigated the effects of electrical stimulation of efferent vagal nerve on myocardial expression and activation of MMPs and TIMPs in a rabbit model of myocardial ischemia- reperfusion (I/R) injury. Anesthetized rabbits were subjected to 60 min of left coronary artery occlusion and 180 min of reperfusion with (I/R-VS, n = 8) or without vagal nerve stimulation (I/R, n = 7). Rabbits not subjected to coronary occlusion with (VS, n = 7) or without vagal stimulation (sham, n = 7) were used as controls. Total MMP-9 protein increased significantly after left coronary artery occlusion in I/R-VS and I/R to a similar degree compared with VS and sham values. Endogenous active MMP- 9 protein level was significantly lower in I/R-VS compared with I/R. TIMP-1 mRNA expression was significantly increased in I/R-VS compared with the I/R, VS, and sham groups. TIMP-1 protein was significantly increased in I/R-VS and VS compared with the I/R and sham groups. Cardiac microdialysis technique demonstrated that topical perfusion of acetylcholine increased dialysate TIMP-1 protein level, which was suppressed by coperfusion of atropine. Immunohistochemistry demonstrated a strong expression of TIMP-1 protein in cardiomyocytes around the dialysis probe used to perfuse acetylcholine. In conclusion, in a rabbit model of myocardial I/R injury, vagal nerve stimulation induced TIMP- 1 expression in cardiomyocytes and reduced active MMP-9.