Yoshida T, Maulik N, Engelman R M, Ho Y S, Das D K
Cardiovascular Research Center, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
Circ Res. 2000 Feb 18;86(3):264-9. doi: 10.1161/01.res.86.3.264.
The role of Cu/Zn-superoxide dismutase (SOD) in myocardial ischemic reperfusion injury was studied by using a mouse model with targeted disruption of the mouse Sod I gene. Inactivation of the functional mouse Sod I gene in hearts by gene targeting (Sod I(+/-)) resulted in a 50% reduction of Cu/Zn-SOD mRNA and significant reduction of Cu/Zn-SOD enzyme activity compared with that of wild-type Sod I(+/+) mice. Cu/Zn-SOD mRNA could not be detected in Sod I(-/-) heart. The isolated buffer-perfused hearts from the knockout mice devoid of any functional copy of the Sod I (Sod I(-/-)) and matched nontransgenic control mice were subjected to 30 minutes of global ischemia followed by 2 hours of reperfusion. For both groups of mice, the postischemic functional recovery for the hearts was lower than the baseline, but the recovery for the Sod I(-/-) was less compared with the wild-type mice. Thus, the postischemic recovery of the developed force and the maximum first derivative of the developed force were consistently lower for the Sod I(-/-) mouse hearts compared with wild-type control hearts. The coronary flow was lower compared with the baseline levels for both groups of hearts, but there was no significant difference between the groups. The myocardial infarction determined from the ratio of infarct size/area of risk was higher for the Sod I(-/-) mice compared with the control mice. The amount of creatine kinase release from the wild-type mouse hearts was less compared with the Sod I(-/-) mouse hearts. In concert, a reduced amount of oxidative stress was found in the hearts of wild-type mice compared with Sod I(-/-) mouse hearts. These results documented that Sod I(-/-) mouse hearts were more susceptible to ischemic reperfusion injury compared with corresponding wild-type mouse hearts, suggesting that the Sod I gene constitutes an important defense element for the hearts.
通过使用对小鼠Sod I基因进行靶向破坏的小鼠模型，研究了铜/锌超氧化物歧化酶（SOD）在心肌缺血再灌注损伤中的作用。通过基因靶向使心脏中的功能性小鼠Sod I基因失活（Sod I(+/-)），与野生型Sod I(+/+)小鼠相比，导致铜/锌-SOD mRNA减少50%，铜/锌-SOD酶活性显著降低。在Sod I(-/-)心脏中未检测到铜/锌-SOD mRNA。将缺乏Sod I任何功能性拷贝的基因敲除小鼠（Sod I(-/-)）和匹配的非转基因对照小鼠分离的缓冲液灌注心脏进行30分钟的全心缺血，然后再灌注2小时。对于两组小鼠，心脏缺血后的功能恢复均低于基线，但与野生型小鼠相比，Sod I(-/-)的恢复程度更低。因此，与野生型对照心脏相比，Sod I(-/-)小鼠心脏缺血后的发育力恢复和发育力的最大一阶导数始终较低。两组心脏的冠状动脉流量均低于基线水平，但两组之间无显著差异。与对照小鼠相比，Sod I(-/-)小鼠的梗死面积/危险面积比值所确定的心肌梗死更高。与Sod I(-/-)小鼠心脏相比，野生型小鼠心脏释放的肌酸激酶量更少。一致的是，与Sod I(-/-)小鼠心脏相比，野生型小鼠心脏中的氧化应激量减少。这些结果证明，与相应的野生型小鼠心脏相比，Sod I(-/-)小鼠心脏对缺血再灌注损伤更敏感，表明Sod I基因构成了心脏的重要防御元件。
