Wang P, Chen H, Qin H, Sankarapandi S, Becher M W, Wong P C, Zweier J L
Molecular and Cellular Biophysics Laboratories, Department of Medicine, Division of Cardiology and the Electron Paramagnetic Resonance Center, The Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD 21224, USA.
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4556-60. doi: 10.1073/pnas.95.8.4556.
Superoxide and superoxide-derived oxidants have been hypothesized to be important mediators of postischemic injury. Whereas copper, zinc-superoxide dismutase, SOD1, efficiently dismutates superoxide, there has been controversy regarding whether increasing intracellular SOD1 expression would protect against or potentiate cellular injury. To determine whether increased SOD1 protects the heart from ischemia and reperfusion, studies were performed in a newly developed transgenic mouse model in which direct measurement of superoxide, contractile function, bioenergetics, and cell death could be performed. Transgenic mice with overexpression of human SOD1 were studied along with matched nontransgenic controls. Immunoblotting and immunohistology demonstrated that total SOD1 expression was increased 10-fold in hearts from transgenic mice compared with nontransgenic controls, with increased expression in both myocytes and endothelial cells. In nontransgenic hearts following 30 min of global ischemia a reperfusion-associated burst of superoxide generation was demonstrated by electron paramagnetic resonance spin trapping. However, in the transgenic hearts with overexpression of SOD1 the burst of superoxide generation was almost totally quenched, and this was accompanied by a 2-fold increase in the recovery of contractile function, a 2.2-fold decrease in infarct size, and a greatly improved recovery of high energy phosphates compared with that in nontransgenic controls. These results demonstrate that superoxide is an important mediator of postischemic injury and that increasing intracellular SOD1 dramatically protects the heart from this injury. Thus, increasing intracellular SOD1 expression may be a highly effective approach to decrease the cellular injury that occurs following reperfusion of ischemic tissues.
超氧化物和超氧化物衍生的氧化剂被认为是缺血后损伤的重要介质。虽然铜锌超氧化物歧化酶（SOD1）能有效地歧化超氧化物，但关于增加细胞内SOD1表达是否能预防或加重细胞损伤一直存在争议。为了确定增加的SOD1是否能保护心脏免受缺血和再灌注损伤，我们在一种新开发的转基因小鼠模型中进行了研究，在该模型中可以直接测量超氧化物、收缩功能、生物能量学和细胞死亡情况。我们研究了过表达人SOD1的转基因小鼠以及配对的非转基因对照小鼠。免疫印迹和免疫组织学结果显示，与非转基因对照小鼠相比，转基因小鼠心脏中的总SOD1表达增加了10倍，心肌细胞和内皮细胞中的表达均有所增加。在非转基因心脏经历30分钟全心缺血后，电子顺磁共振自旋捕捉技术证实了再灌注相关的超氧化物生成爆发。然而，在过表达SOD1的转基因心脏中，超氧化物生成爆发几乎完全被抑制，与此同时，与非转基因对照小鼠相比，收缩功能恢复增加了2倍，梗死面积减小了2.2倍，高能磷酸盐的恢复也有显著改善。这些结果表明，超氧化物是缺血后损伤的重要介质，增加细胞内SOD1能显著保护心脏免受这种损伤。因此，增加细胞内SOD1表达可能是一种非常有效的方法，可减少缺血组织再灌注后发生的细胞损伤。
