ROS are oxygen‐based chemical species characterised by their high reactivity. They include free radicals (ie, species with
1 unpaired electrons, such as superoxide (O2.−
) and hydroxyl (OH.
) and non‐radicals capable of generating free radicals (eg, hydrogen peroxide (H2
); fig 1). If present in excess, free radicals can induce oxidation and damage to DNA, membranes, proteins and other macromolecules. Diverse specific and non‐specific antioxidant defence systems therefore exist to scavenge and degrade ROS to non‐toxic molecules.5
The balance between ROS production and their removal by antioxidant systems describes the “redox state” of a cell; a pathological imbalance in favour of excess ROS is termed oxidative stress. A small amount of O2.−
is normally produced as a byproduct of the use of molecular oxygen during mitochondrial oxidative phosphorylation. A family of superoxide dismutase enzymes rapidly converts O2.−
, which is itself broken down by glutathione peroxidase and catalase to water. Under pathological conditions, the single‐electron reduction of H2
may lead to the formation of highly reactive OH radicals (fig 1).
Figure 1Key reactions underlying the formation and degradation of hydrogen peroxide (H2O2). O2.−, superoxide; OH., hydroxyl; SOD, superoxide dismutase; GPx, glutathione peroxidase.
The pathophysiological effects of ROS depend on the type, concentration and specific site of production and involve three broad types of action (fig 2). When the local levels of ROS are high, they tend to react with numerous protein centres, DNA, cell membranes and other molecules, causing considerable cellular damage as well as generating other more reactive radicals. At lower concentrations, however, local targeted production of ROS serves as a second‐messenger system that transmits biological information through the highly specific modulation of intracellular signalling molecules, enzymes and proteins. This so‐called redox signalling function is especially true for the ROS, H2
, which is more stable and diffusible than radical species such as O2.−
, but also applies to nitric oxide. Redox signalling processes are involved in the activation of many signal transduction protein kinases and transcription factors, the stimulation of DNA synthesis and expression of growth‐related genes,3,5
and the regulation of myocardial excitation–contraction coupling.6
The third general ROS‐related pathophysiological mechanism involves the reaction of O2.−
with the signalling molecule nitric oxide, which in health has a central role in vascular homeostasis as well as in modulating cardiac function. The reaction between O2.−
and nitric oxide leads to inactivation of nitric oxide and loss of its biological activity as well as the generation of the peroxynitrite (ONOO−
The reaction is especially likely to occur when both O2.−
and nitric oxide levels are high and antioxidant activity is low. Interestingly, although high levels of ONOO−
may induce non‐specific toxic effects, at lower levels this species is itself capable of modulating signalling events in vivo, indicating an additional level of complexity.
Figure 2Main pathophysiological effects of oxidative stress in heart failure. ROS, reactive oxygen species; NO, nitric oxide.