Submitted on April 24, 2007
Accepted on August 7, 2007
Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit
Kazunori Uemura1*, Meihua Li2, Takaki Tsutsumi3, Toji Yamazaki4, Toru Kawada2, Atsunori Kamiya2, Masashi Inagaki2, Kenji Sunagawa3, and Masaru Sugimachi2
1 Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka, 565-8565, Japan
2 Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
3 Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Science, Fukuoka, Fukuoka, Japan
4 Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
* To whom correspondence should be addressed. E-mail: kuemura{at}ri.ncvc.go.jp.
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 injury. Anesthetized rabbits were subjected to 60 min of left coronary artery occlusion and 180 min of reperfusion with (IR-VS, n=8) or without vagal nerve stimulation (IR, 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 IR-VS and IR to a similar degree, compared to VS and Sham values. Endogenous active MMP-9 protein level was significantly lower in IR-VS compared to IR. TIMP-1 mRNA expression was significantly increased in IR-VS compared to IR, VS and Sham. TIMP-1 protein was significantly increased in IR-VS and VS compared to IR and Sham. Cardiac microdialysis technique demonstrated that topical perfusion of acetylcholine increased dialysate TIMP-1 protein level, which was suppressed by co-perfusion of atropine. Immunohistochemistry demonstrated strong expression of TIMP-1 protein in cardiomyocytes around the dialysis probe used to perfuse acetylcholine. In conclusion, in a rabbit model of myocardial ischemia-reperfusion injury, vagal nerve stimulation induced TIMP-1 expression in cardiomyocytes and reduced active MMP-9.
