Giricz Zoltán, Lalu Manoj M, Csonka Csaba, Bencsik Péter, Schulz Richard, Ferdinandy Péter
Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, H-6720 Szeged, Hungary.
J Pharmacol Exp Ther. 2006 Jan;316(1):154-61. doi: 10.1124/jpet.105.091140. Epub 2005 Sep 15.
Hyperlipidemia attenuates the cardioprotective effect of preconditioning via unknown mechanisms. We have reported previously that in normolipidemic rats, preconditioning decreased ischemia-induced activation and release of myocardial matrix metalloproteinase (MMP)-2 into the coronary perfusate. Here, we investigated whether hyperlipidemia interferes with the cardioprotective effect of preconditioning through modulation of MMP-2. Hearts isolated from male Wistar rats fed 2% cholesterol-enriched or control chow for 9 weeks were subjected to a preconditioning protocol (three intermittent periods of ischemia/reperfusion of 5-min duration each) or a time-matched nonpreconditioning protocol. This was followed by a test ischemia/reperfusion (30-min ischemia and 120-min reperfusion) in both groups. Preconditioning decreased infarct size in the control but not the cholesterol-fed group. Cardioprotection in the preconditioned control group but not in the cholesterol-fed group was associated with an 18 +/- 3% (p < 0.05) inhibition of test ischemia/reperfusion-induced activation and release of myocardial MMP-2 into the perfusate. Myocardial protein levels of tissue inhibitors of MMPs [tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4] were not changed in either group. A reduction of infarct size in nonpreconditioned hearts from both control and cholesterol-fed group was produced by the MMP inhibitor ilomastat at 0.25 microM, a concentration producing MMP-2 inhibition comparable with that of preconditioning in the control group. We conclude that hyperlipidemia blocks preconditioning-induced cardioprotection, hyperlipidemia abolishes preconditioning-induced inhibition of myocardial MMP-2 activation and release, preconditioning-induced inhibition of MMP-2 activation and release is not mediated by TIMPs, and pharmacological inhibition of MMPs produces cardioprotection in both normal and hyperlipidemic rats.
高脂血症通过未知机制减弱预处理的心脏保护作用。我们之前报道过，在血脂正常的大鼠中，预处理可降低缺血诱导的心肌基质金属蛋白酶（MMP）-2的激活及向冠状动脉灌注液中的释放。在此，我们研究了高脂血症是否通过调节MMP-2来干扰预处理的心脏保护作用。将雄性Wistar大鼠分为两组，分别喂食富含2%胆固醇的饲料或对照饲料9周，然后对分离出的心脏进行预处理方案（三个5分钟时长的间歇性缺血/再灌注期）或时间匹配的非预处理方案。之后两组均进行测试性缺血/再灌注（30分钟缺血和120分钟再灌注）。预处理可减小对照组的梗死面积，但对喂食胆固醇组无效。预处理对照组而非喂食胆固醇组的心脏保护作用与测试性缺血/再灌注诱导的心肌MMP-2向灌注液中的激活及释放受到18±3%（p<0.05）的抑制相关。两组心肌中MMP组织抑制剂[金属蛋白酶组织抑制剂（TIMP）-2和TIMP-4]的蛋白水平均未改变。0.25微摩尔的MMP抑制剂伊洛马司他可减小对照组和喂食胆固醇组非预处理心脏的梗死面积，该浓度产生的MMP-2抑制作用与对照组预处理相当。我们得出结论：高脂血症会阻断预处理诱导的心脏保护作用，高脂血症会消除预处理诱导的对心肌MMP-2激活及释放的抑制，预处理诱导的对MMP-2激活及释放的抑制不是由TIMPs介导的，并且MMP的药理学抑制在正常和高脂血症大鼠中均可产生心脏保护作用。
