Oka Norihiko, Wang Lixing, Mi Wenyu, Caldarone Christopher A
The Division of Cardiovascular Surgery at the Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
J Thorac Cardiovasc Surg. 2008 Mar;135(3):585-93. doi: 10.1016/j.jtcvs.2007.09.023.
Mitochondrial permeability transition pore opening is associated with apoptotic signaling and alterations in mitochondrial structure and function. We tested whether inhibition of mitochondrial permeability transition pore opening with cyclosporine A preserved mitochondrial structure and function after cardioplegic arrest and whether this preservation is associated with improved myocardial performance.
Langendorff-perfused neonatal rabbit hearts were perfused for 30 minutes with Krebs-Henseleit buffer (CCP; n = 6) or Krebs-Henseleit buffer containing 2 mumol/L of cyclosporine A (CCP+CsA; n = 6) followed by 60 minutes of normothermic crystalloid cardioplegia (CCP) and 60 minutes of reperfusion. Control hearts (non-CCP; n = 6) were constantly perfused for 150 minutes without cardioplegic arrest.
In comparison with non-CCP, CCP was associated with Bax translocation to the mitochondria, cytochrome c release, and greater frequency of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive myocytes These changes were also associated with deficits in isolated mitochondrial oxygen consumption at complex I. CsA pretreatment minimized or prevented all these findings. Myocardial performance (systolic pressure, maximum positive and negative dP/dt, and elevated left ventricular end-diastolic pressure) at 5, 15, 30, and 60 minutes after reperfusion was diminished in CCP hearts when compared with non-CPB, and these deficits could be minimized with cyclosporine A pretreatment. (P < .05 all comparisons)
Cyclosporine A prevents apoptosis-related mitochondrial permeabilization and dysfunction after cardioplegic arrest. This protection is associated with improved myocardial performance. Prevention of mitochondrial permeability transition pore opening is a valuable target for mitochondrial (and myocardial) preservation after neonatal cardioplegic arrest.
线粒体通透性转换孔开放与凋亡信号传导以及线粒体结构和功能改变有关。我们测试了用环孢素A抑制线粒体通透性转换孔开放是否能在心脏停搏后保留线粒体结构和功能，以及这种保留是否与改善心肌性能相关。
用Krebs-Henseleit缓冲液（CCP；n = 6）或含2 μmol/L环孢素A的Krebs-Henseleit缓冲液（CCP+CsA；n = 6）对Langendorff灌注的新生兔心脏灌注30分钟，随后进行60分钟常温晶体心脏停搏（CCP）和60分钟再灌注。对照心脏（非CCP；n = 6）持续灌注150分钟，无心脏停搏。
与非CCP相比，CCP与Bax转位至线粒体、细胞色素c释放以及末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性心肌细胞的频率增加有关。这些变化还与复合体I处分离线粒体的氧消耗不足有关。CsA预处理使所有这些发现最小化或得到预防。与非CPB相比，CCP心脏在再灌注后5、15、30和60分钟时的心肌性能（收缩压、最大正负dP/dt以及升高的左心室舒张末期压力）降低，而环孢素A预处理可使这些缺陷最小化。（所有比较P < 0.05）
环孢素A可预防心脏停搏后凋亡相关的线粒体通透性改变和功能障碍。这种保护与改善心肌性能相关。预防线粒体通透性转换孔开放是新生儿心脏停搏后线粒体（和心肌）保护的一个有价值的靶点。
