Kristián T, Siesjö B K
Center for the Study of Neurological Disease, The Queen's Medical Center, Honolulu, Hawaii 96813, USA.
Stroke. 1998 Mar;29(3):705-18. doi: 10.1161/01.str.29.3.705.
This review article deals with the role of calcium in ischemic cell death. A calcium-related mechanism was proposed more than two decades ago to explain cell necrosis incurred in cardiac ischemia and muscular dystrophy. In fact, an excitotoxic hypothesis was advanced to explain the acetylcholine-related death of muscle end plates. A similar hypothesis was proposed to explain selective neuronal damage in the brain in ischemia, hypoglycemic coma, and status epilepticus.
The original concepts encompass the hypothesis that cell damage in ischemia-reperfusion is due to enhanced activity of phospholipases and proteases, leading to release of free fatty acids and their breakdown products and to degradation of cytoskeletal proteins. It is equally clear that a coupling exists between influx of calcium into cells and their production of reactive oxygen species, such as .O2, H2O2, and .OH. Recent results have underscored the role of calcium in ischemic cell death. A coupling has been demonstrated among glutamate release, calcium influx, and enhanced production of reactive metabolites such as .O2-, .OH, and nitric oxide. It has become equally clear that the combination of .O2- and nitric oxide can yield peroxynitrate, a metabolite with potentially devastating effects. The mitochondria have again come into the focus of interest. This is because certain conditions, notably mitochondrial calcium accumulation and oxidative stress, can trigger the assembly (opening) of a high-conductance pore in the inner mitochondrial membrane. The mitochondrial permeability transition (MPT) pore leads to a collapse of the electrochemical potential for H+, thereby arresting ATP production and triggering production of reactive oxygen species. The occurrence of an MPT in vivo is suggested by the dramatic anti-ischemic effect of cyclosporin A, a virtually specific blocker of the MPT in vitro in transient forebrain ischemia. However, cyclosporin A has limited effect on the cell damage incurred as a result of 2 hours of focal cerebral ischemia, suggesting that factors other than MPT play a role. It is discussed whether this could reflect the operation of phospholipase A2 activity and degradation of the lipid skeleton of the inner mitochondrial membrane.
Calcium is one of the triggers involved in ischemic cell death, whatever the mechanism.
这篇综述文章探讨了钙在缺血性细胞死亡中的作用。二十多年前就提出了一种与钙相关的机制来解释心脏缺血和肌肉营养不良中发生的细胞坏死。事实上，有人提出了一种兴奋性毒性假说，以解释肌肉终板与乙酰胆碱相关的死亡。人们还提出了类似的假说，以解释缺血、低血糖昏迷和癫痫持续状态时大脑中选择性神经元损伤的原因。
最初的概念包括这样一种假说，即缺血再灌注中的细胞损伤是由于磷脂酶和蛋白酶活性增强，导致游离脂肪酸及其分解产物的释放以及细胞骨架蛋白的降解。同样清楚的是，钙流入细胞与其活性氧的产生之间存在耦合，例如超氧阴离子（.O2）、过氧化氢（H2O2）和羟自由基（.OH）。最近的研究结果强调了钙在缺血性细胞死亡中的作用。已经证明谷氨酸释放、钙流入与活性代谢产物如超氧阴离子（.O2-）、羟自由基（.OH）和一氧化氮的产生增加之间存在耦合。同样清楚的是，超氧阴离子（.O2-）和一氧化氮的结合可产生过氧亚硝酸盐，这是一种具有潜在破坏性影响的代谢产物。线粒体再次成为人们关注焦点。这是因为某些情况，特别是线粒体钙积累和氧化应激，可触发线粒体内膜高电导孔的组装（开放）。线粒体通透性转换（MPT）孔导致H+电化学势崩溃，从而停止ATP生成并触发活性氧的产生。环孢素A在体内具有显著的抗缺血作用，它在体外是MPT的一种几乎特异性的阻滞剂，这提示了体内MPT的发生。然而，环孢素A对2小时局灶性脑缺血所致的细胞损伤作用有限，这表明除MPT外的其他因素也起作用。文章讨论了这是否可能反映磷脂酶A2活性的作用以及线粒体内膜脂质骨架的降解。
无论机制如何，钙都是缺血性细胞死亡的触发因素之一。
