Ischemic Cell Death; Mechanisms
Ischemia leads to energy failure and a series of primary effects that encompass depolarization, release of glutamate from cells, and their uptake of Ca 2+ (and Zn 2+ ). This secondarily leads to a cascade of calcium-induced biochemical changes that involve degradation of lipids, deoxyribonucleic acid (DNA), and proteins, as well as changes in protein phosphorylation and gene expression. Some of the reactions elicited lead to the production of reactive oxygen species (ROS), nitric oxide, and peroxynitrate, which cause lipid peroxidation, protein oxidation, and nitrosylation, as well DNA damage. An important effect of calcium accumulation and formation of ROS and peroxynitrate is mitochondrial membrane damage, which triggers the formation of a mitochondrial permeability transition with release of cytochrome c (cyt c ), resulting in caspase-mediated cell death. Delayed cell death is probably the result of gene expression, with induction of enzymes mediating an inflammatory and immunological response, and signal transduction changes that upregulate proapoptotic member of the Bcl-2 family of proteins or downregulate the antiapoptotic ones.