Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit

Departments of 1 Cardiovascular Dynamics and 3 Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Japan; and 2 Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Science, Fukuoka, Japan Submitted 24 April 2007 ; accepted in final form 7 August 2007 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. myocardial remodeling; matrix metalloproteinase; acetylcholine Address for reprint requests and other correspondence: K. Uemura, Dept. of Cardiovascular Dynamics, National Cardiovascular Center Research Inst., 5-7-1 Fujishirodai, Suita 565-8565, Japan (e-mail: kuemura{at}ri.ncvc.go.jp )