Lim Shiang Y, Davidson Sean M, Hausenloy Derek J, Yellon Derek M
The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London WC1E 6HX, UK.
Cardiovasc Res. 2007 Aug 1;75(3):530-5. doi: 10.1016/j.cardiores.2007.04.022. Epub 2007 May 4.
The opening of the mitochondrial permeability transition pore (mPTP) at the time of myocardial reperfusion is a critical determinant of cell death. Emerging studies suggest that suppression of mPTP opening may underlie the cardioprotection elicited by both ischemic preconditioning (IPC) and postconditioning (IPost). To further evaluate the role of the mPTP in cardioprotection, we hypothesized that hearts deficient in cyclophilin-D (CYP-D-/-), a key component of the mPTP, will be resistant to cardioprotection conferred by ischemic and pharmacological preconditioning and postconditioning.
Male/female wild type or CYP-D-/- mice were subjected to 30 min of ischemia and 120 min of reperfusion. In wild type mice subjected to in vivo myocardial ischemia-reperfusion injury, a significant reduction in myocardial infarct size was observed with the following treatments (n>/=6/group; P<0.05): (1) IPC (28+/-4% vs. 46.2+/-4% in control); (2) Diazoxide (5 mg/kg) pre-treatment (26.4+/-3% vs. 54+/-10% in vehicle control); (3) IPost-1 or IPost-2, three or six 10-s cycles of ischemia-reperfusion (27.2+/-3% and 32+/-4%, respectively vs. 46.2+/-4% in control); (4) Bradykinin (40 mug/kg) (28.3+/-1% vs. 48+/-4% in vehicle control); (5) cyclosporin-A (10 mg/kg) (32.3+/-3% vs. 48+/-4% in vehicle control) (6) sanglifehrin-A (25 mg/kg) (29.3+/-3% vs. 48+/-4% in vehicle control). Interestingly, however, no infarct-limiting effects were demonstrated in CYP-D-/- mice with the same treatment protocols: (27.9+/-5% in control vs. 31.2+/-7% with IPC, 30.2+/-5% with IPost-1, 24.7+/-8% with IPost-2; 30.1+/-4% in vehicle control vs. 26.4+/-7% with diazoxide; 24.6+/-4% in vehicle control vs. 24.9+/-5% with bradykinin, 26.8+/-7% with cyclosporin-A, 32.5+/-6% with sanglifehrin-A: n>/=6/group: P>0.05).
This study demonstrates that the mPTP plays a critical role in the cardioprotection elicited by ischemic and pharmacological preconditioning and postconditioning.
心肌再灌注时线粒体通透性转换孔（mPTP）的开放是细胞死亡的关键决定因素。新出现的研究表明，抑制mPTP开放可能是缺血预处理（IPC）和后处理（IPost）所引发心脏保护作用的基础。为了进一步评估mPTP在心脏保护中的作用，我们假设亲环蛋白-D（CYP-D-/-）缺陷的心脏，mPTP的一个关键组成部分，将对缺血和药物预处理及后处理所赋予的心脏保护作用具有抗性。
雄性/雌性野生型或CYP-D-/-小鼠经历30分钟缺血和120分钟再灌注。在经历体内心肌缺血-再灌注损伤的野生型小鼠中，以下处理观察到心肌梗死面积显著减小（每组n≥6；P<0.05）：（1）IPC（对照组为46.2±4%，处理组为28±4%）；（2）二氮嗪（5mg/kg）预处理（载体对照组为54±10%，处理组为26.4±3%）；（3）IPost-1或IPost-2，三个或六个10秒的缺血-再灌注周期（对照组为46.2±4%，IPost-1组为27.2±3%，IPost-2组为32±4%）；（4）缓激肽（40μg/kg）（载体对照组为48±4%，处理组为28.3±1%）；（5）环孢素A（10mg/kg）（载体对照组为48±4%，处理组为32.3±3%）（6）桑吉弗林A（25mg/kg）（载体对照组为48±4%，处理组为29.3±3%）。然而，有趣的是，采用相同处理方案的CYP-D-/-小鼠未显示梗死限制效应：（对照组为27.9±5%，IPC组为31.2±7%，IPost-1组为30.2±5%，IPost-2组为24.7±8%；载体对照组为30.1±4%，二氮嗪处理组为26.4±7%；载体对照组为24.6±4%，缓激肽处理组为24.9±5%，环孢素A处理组为26.8±7%，桑吉弗林A处理组为32.5±6%：每组n≥6；P>0.05）。
本研究表明，mPTP在缺血和药物预处理及后处理所引发的心脏保护中起关键作用。
