Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Diseases

Reactive oxygen species (ROS) include a wide variety of molecules and free radicals derived from molecular oxygen. O2 being highly electrophilic can be reduced by one electron at a time producing relatively stable intermediates, such as superoxide anion (O2• ̄), precursor of most ROS and a relevant mediator in many biological reactions. Dismutation of O2• ̄ produces hydrogen peroxide (H2O2), which, in turn, may be fully reduced to water or partially reduced to hydroxyl radical (•OH), one of the strongest oxidants in nature. The formation of •OH is catalyzed by reduced transition metals. On the other hand, superoxide anion is able to reduce transition metals and intensify in this way hydroxyl generation. In addition, O2• ̄ may react with other radicals, in particular, with nitric oxide (•NO) in a reaction controlled by the rate of diffusion of both radicals. The product, peroxynitrite, is very powerful oxidant. The oxidants derived from •NO have been recently called reactive nitrogen species (RNS). Oxidative stress is an expression used to describe various deleterious processes resulting from an imbalance between the formation and elimination of ROS and/or RNS by antioxidant defenses. While small fluctuations in the steady-state concentration of these oxidants play an important role in intracellular signaling, uncontrolled increase in their concentration produces free radical-mediated chain reactions, which indiscriminately target proteins, lipids, polysaccharides, and DNA. Mitochondria are a major source of ROS, converting as much as 0.2-2% of molecular oxygen to superoxide as a by-product of the electron transfer activity (Wittenberg & Wittenberg, 1989; Alvárez et al., 2003). Other enzymatic sources of ROS include NADPH oxidases, located on the cell membrane of polymorphonuclear cells, macrophages, endothelial and other cells, and cytochrome P450-dependent oxygenases, along with the proteolytic conversion of xanthine dehydrogenase to xanthine oxidase, which produces both O2• ̄ and H2O2.