Molecular Biology of Apoptosis in Ischemia and Reperfusion

Abstract

This study reviews the current understanding of the mechanisms that mediate the complex processes involved in apoptosis secondary to ischemia and reperfusion (I/R) and is not intended as a complete literature review of apoptosis. Several biochemical reactions trigger a cascade of events, which activate caspases. These caspases exert their effect through downstream proteolysis until the final effector caspases mediate the nuclear features characteristic of apoptosis, DNA fragmentation and condensation. Within the context of ischemia, the hypoxic environment initiates the expression of several genes involved in inflammation, the immune response, and apoptosis. Many of these same genes are activated during reperfusion injury in response to radical oxygen species generation. It is plausible that inhibition of specific apoptotic pathways via inactivation or downregulation of those genes responsible for the initiation of inflammation, immune response, and apoptosis may provide promising molecular targets for ameliorating reperfusion injury in I/R-related processes. Such inhibitory mechanisms are discussed in this review. Important targets in I/R-related pathologies include the brain during stroke, the heart during myocardial infarction, and the organs during harvesting and/or storage for transplantation. In addition, we present data from our ongoing research of specific signal transduction-related elements and their role in ischemia/reperfusion injury. These data address the potential therapeutic application of anti-inflammatory and anti-ischemic compounds in the prevention of I/R damage.

HIV protease inhibitors modulate apoptosis signaling in vitro and in vivo

“…Damage is not evident until hours, days, and weeks following reperfusion when cells begin to exhibit many of the morphological and biochemical characteristics of apoptosis [45]. Death is likely triggered during ischemia/reperfusion by downstream release of internal calcium stores from endoplasmic reticulum and mitochondria [43]. Additional death pathways are subsequently initiated by a complex cross-talk between extrinsic death receptor mediated-induction and intrinsic mitochondrialdependent pathways.…”

“…Neuronal depolarization resulting from a loss of calcium homeostasis is further exacerbated by the sustained release of glutamate and reduction in extracellular pH leading to excitotoxicity. Production of free fatty acids and oxyradicals are elevated, triggering oxidative remodeling of membrane lipids, impaired glial homeostatic functions and enhanced inflammatory cell activation [40,43,44].…”

“…Release of reactive oxygen species following ischemic reperfusion triggers release of cytochrome c and ATP from compromised mitochondria into the cytosol, often with concomitant loss of loss of y m . Activation of caspase 9 occurs with formation of the apoptosome composed of APAF-1, cytochrome c, ATP, and procaspase 9 resulting in downstream activation of caspase-3, -6, -7 [43,46].…”

Protective effects of ginsenoside Rb3 on oxygen and glucose deprivation-induced ischemic injury in PC12 cells

“…Neuronal injury induced by cerebral ischemia/reperfusion, is a very complex process with multiple mechanism, such as excitotoxicity, oxidative stress, apoptosis, and variations in gene expression or the activation of kinase [2,3] . Mitochondria are vital cell organs in the process of transmitting apoptosis signs through releasing apoptotic factors into the cytosol [4,5] , ischemia/reperfusion-induced mitochondrial dysfunction plays a central role in cell death through controlling cellular energy metabolism. Mitochondrium was recently believed to be a good therapeutic target for the cerebral ischemia [6] .…”

Sildenafil citrate protects skeletal muscle of ischemia-reperfusion injury: immunohistochemical study in rat model

“…Necrosis used to be considered the solo mechanism in ischemic conditions, but current evidence show apoptosis as the major contributor to cell death due to IRI 3,4 .…”