Uemura Kazunori, Li Meihua, Tsutsumi Takaki, Yamazaki Toji, Kawada Toru, Kamiya Atsunori, Inagaki Masashi, Sunagawa Kenji, Sugimachi Masaru
Dept. of Cardiovascular Dynamics, National Cardiovascular Center Research Inst., 5-7-1 Fujishirodai, Suita 565-8565, Japan.
Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2254-61. doi: 10.1152/ajpheart.00490.2007. Epub 2007 Aug 10.
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.
迷走神经刺激已被认为可改善心力衰竭中的左心室（LV）重塑。然而，尚不清楚迷走神经刺激是否以及在何种程度上影响心肌中的基质金属蛋白酶（MMP）和MMP组织抑制剂（TIMP），已知它们在LV重塑中起关键作用。因此，我们在心肌缺血再灌注（I/R）损伤的兔模型中研究了传出迷走神经电刺激对心肌MMPs和TIMPs表达及激活的影响。将麻醉的兔子进行60分钟的左冠状动脉闭塞和180分钟的再灌注，其中一组接受迷走神经刺激（I/R-VS，n = 8），另一组不接受迷走神经刺激（I/R，n = 7）。未进行冠状动脉闭塞的兔子，一组接受迷走神经刺激（VS，n = 7），另一组不接受迷走神经刺激（假手术组，n = 7）作为对照。与VS组和假手术组的值相比，I/R-VS组和I/R组在左冠状动脉闭塞后总MMP-9蛋白显著增加，且增加程度相似。与I/R组相比，I/R-VS组内源性活性MMP-9蛋白水平显著降低。与I/R组、VS组和假手术组相比，I/R-VS组中TIMP-1 mRNA表达显著增加。与I/R组和假手术组相比，I/R-VS组和VS组中TIMP-1蛋白显著增加。心脏微透析技术表明，局部灌注乙酰胆碱可增加透析液中TIMP-1蛋白水平，而阿托品共同灌注可抑制该作用。免疫组织化学显示，在用于灌注乙酰胆碱的透析探针周围的心肌细胞中，TIMP-1蛋白表达强烈。总之，在心肌I/R损伤的兔模型中，迷走神经刺激诱导心肌细胞中TIMP-1表达并降低活性MMP-9。
