Enhanced production of oxygen radicals during ischemia/reperfusion can overwhelm endogenous defense mechanisms and lead to damage of lipids, proteins, and DNA. Superoxide dismutase (SOD) isoforms located in the cytosol, mitochondria, and extracellular membrane convert the superoxide radical to hydrogen peroxide, which is then metabolized by cata-lase. Superoxide is a normal byproduct of mitochondrial respiration, but Ca2+ overload in mitochondria during ischemia leads to electron transport uncoupling and excessive superoxide production. A role for superoxide in global ischemia is supported by the observations that decreasing the expression of the cytosolic Cu,Zn-SOD augments hippocampal injury from global ischemia (95), whereas increasing expression reduces activation of proapoptotic signaling from the mitochondria and alleviates neuronal injury (96,97).
Iron can be mobilized by the action of superoxide on ferritin (98) and by the action of lactic acid on bicarbonate bridges on transferrin (99). Iron can catalyze hydroxyl radical formation by the Fenton reaction and participate in other free radical reactions (100 ) . A role for iron-induced injury is implicated by a mobilization of iron from its storage proteins and a beneficial effect of the iron chelator deferoxamine in sustaining energy metabolism after severe acidotic ischemia (101,102).
Peroxynitrite is considered to be a major source of hydroxyl radical formation during ischemia/reperfusion (103-105). Peroxynitrite is formed in the presence of superoxide and NO, both of which are abundant during reperfusion. Protection seen with increased SOD activity and decreased nNOS activity are thought to be linked to decreased peroxynitrite formation. Free radical reactions initiated by peroxynitrite are implicated in damage to DNA, lipids, and proteins and to nitration of tyrosine residues that may alter protein function (106).
Conversion of xanthine dehydrogenase to xanthine oxidase by Ca2+-activated proteases can lead to increased superoxide formation. This enzyme is enriched in endothelium and may contribute to recruitment of leukocytes and the inflammatory response. Protection by allopu-rinol from hypoxia-ischemia in newborn rats suggests that this pathway may be particularly important in immature brain (107) . However, whether conversion of xanthine dehydroge-nase to xanthine oxidase occurs in mature brain after cerebral ischemia is unclear (108,109 ). Beneficial effects of allopurinol and oxypurinol may be related to preventing loss of adenine nucleotides (110 ).
During inflammation, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in leukocytes is a major source of superoxide. More recently, superoxide generated by NADPH oxidase has been studied as a physiologic signaling molecule in endothelium (111). Impaired cerebrovascular reactivity associated with angiotensin-mediated hypertension and increased P-amyloid has been attributed to increased NADPH oxidase activity (112). The role of NADPH oxidase isoforms that are present in neurons, endothelium, microglia, and macrophages has not been well characterized in global ischemic injury. However, vascular dysfunction after global ischemia is anticipated to be augmented in patients with underlying hypertension, Alzheimer's disease, and diabetes, in part, because of elevated vascular superoxide production.
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Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...