Beyond Reactive Oxygen Species

Abstract

See related articles, pages 1118–1127 Reactive oxygen species (ROS) are generated either during oxidative metabolism or in defense against pathogens. Their production is increased further by tissue injury or disease. Extensive evidence accumulated during the last 30 years provides compelling evidence that ROS-induced damage is a significant cause of cardiovascular injury and dysfunction. A variety of enzymatic and nonenzymatic antioxidants have evolved to protect against the constant onslaught of ROS, and these defenses respond deftly to changes in ROS generation or to the generation of secondary oxidation products. In this issue of Circulation Research , Endo et al1 report that increased mitochondrial accumulation of aldehydes derived from lipid oxidation protects against myocardial ischemia/reperfusion injury. These findings put a new twist on our view of the oxidant–antioxidant balance in the heart and underscore the importance of hormesis in which mild exposure to a stressor elicits an adaptive response that increases resistance to subsequent stress. Understanding how endogenous defense mechanisms are enhanced by stress response signaling could lead to the development of new strategies for combating oxidative stress. Most biological ROS are highly reactive and, therefore, short-lived. The ones with the greatest reactivity, such as the hydroxyl and alkoxyl radicals, have the shortest life span. As a result, the damage they induce is likely to be restricted to their site of origin and, therefore, of limited significance. Hence, it has long been suspected that ROS generate secondary products that spread injury and amplify damage. Which molecules can amplify and propagate ROS-initiated injury? Although many possibilities exist, one likely class of molecules may be aldehydes generated by the oxidation of unsaturated lipids. With the exception of antioxidants such as vitamin E or glutathione, unsaturated lipids are the most likely targets of ROS. When oxidized, these lipids generate a plethora of bioactive …