Redox Stress and the Contributions of BH3-Only Proteins to Infarction

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Abstract
Ischemia followed by reperfusion is the primary cause of tissue injury and infarction during heart attack and stroke. The initiating stimulus is believed to involve reactive oxygen species that are produced during reperfusion when electron transport resumes in the mitochondria after suppression by ischemia. Programmed death has been shown to be a significant component of infarction, and evidence indicates that multiple pathways are initiated during both ischemia and reperfusion phases. Major infarction is preceded by severe ischemia that includes hypoxia, intracellular acidosis, glucose depletion, loss of ATP, and elevation of cytoplasmic calcium. The superimposition of a reactive oxygen surge on the latter condition provides the impetus for maximal damage. Compelling evidence implicates mitochondria not only as the source of initiating ROS but also as the focal sensors that translate the redox stress signal into a cellular-death response. Pivotal to this response are the BH3-only proteins that are activated by death signals and regulate mitochondrial communication with executioner proteins in the cytoplasm. The BH3-only proteins do this by controlling the activity of pores and channels in the outer mitochondrial membrane. To date at least six BH3-only proteins have been shown to contribute to ischemia–reperfusion death pathways in heart and/or brain; these include Bnip3, PUMA, Bid, Bad, HGTD-P, and Noxa. Here we review the evidence for these cell-death pathways and discuss their relevance to ischemic disease and infarction.