Reactive oxygen species: finding the right balance.

Appropriate regulation of reactive oxygen species (ROS) has a significant impact on health and disease. ROS includes oxygen ions (O2̇) free radicals (superoxide [O, 2] and hydroxyl radicals), and peroxides (hydrogen peroxide [H2O2]) and are the products of normal oxygen consuming metabolic process in the body. ROS are small and highly reactive molecules with important cell signaling roles when maintained at proper cellular concentrations. During times of cell stress ROS levels can greatly increase. Because of their highly reactive nature, ROS can modify other oxygen species, proteins, or lipids, a situation often termed oxidative stress. Maintaining normal cellular ROS concentrations is, therefore, vital to the proper physiological function of numerous cell types throughout the body. An excess production or decreased scavenging of ROS has been implicated in the pathogenesis of diverse diseases such as neurodegeneration, diabetes, cancer, and atherosclerosis. Kisucka et al now demonstrate that peroxiredoxin1 (Prdx1) has an important role in the maintenance of endothelial ROS.1 Prdx1 is an antioxidant enzyme that reduces H2O2, lipid peroxides, and peroxynitrite. Prior studies have shown that Prdx1 / mice develop late onset hemolytic anemia and have increased frequency of cancer2 caused by an increase in ROS (such as H2O2), emphasizing the importance of Prdx1 in normal vascular homeostasis. Like many ROS, H2O2 can have disparate effects depending on the cell type and its local concentration. H2O2 can have normal regulatory functions as a second messenger molecule in signal transduction such as in the mitogen-activated protein kinase pathway. H2O2 makes a good signaling molecule because of its reactive nature and its ease of scavenging by antioxidant enzymes such as Prdx1 making for rapid signaling activation and inactivation. H2O2 can also be a source of oxidative stress and vascular injury. Excess H2O2 has been implicated in nitric oxide (NO) dysregulation and mitogenic activities that lead to intimal hyperplasia. In this study, the authors demonstrate that a loss of Prdx1 accelerates the development of atherosclerosis in part by disrupting normal regulation of Weibel–Palade body release resulting in an increase in white blood cell (WBC) interactions with the vasculature.1 ROS in Vascular Biology Endothelial cells form the vital interface between blood constituents and the vessel wall. A loss of endothelial cells leads to thrombus formation and vessel occlusion. Alterations in maintaining endothelial cells in a quiescent state leads to an increase in endothelial cell interactions with platelets and WBC, stimulating more endothelial activation and leukocyte trafficking. Dysregulation of ROS homeostasis can lead to endothelial cell dysfunction. Vascular cells themselves are sources of ROS production. The primary enzymatic sources for vascular oxygen species production are xanthine oxidase, NADH/NADPH oxidase isoforms, and endothelial NO synthase.3 There must be a balance maintained between the production of ROS and the scavenging of ROS. Some of the important scavengers include superoxide dismutase, glutathione, thioredoxin, and peroxiredoxins.3 Oxygen species, such as NO, are important players in maintaining normal physiology. NO helps to maintain vascular tone, inhibits endothelial cell stimulation, and is a regulator of platelet activation.4,5 NO also has a key physiological role as a second messenger in cell signaling in neurons and macrophages. A lack of NO therefore can have significant physiological effects, and excessive NO can also contribute to cell injury by combining with superoxide to produce damaging peroxynitrite. Kisucka et al demonstrated that Prdx1 has a functional role in endothelial cells and a lack of Prdx1 leads to an increase in WBC interactions with endothelial cells.1 This implies that Prdx1 / mice have an endothelial dysfunction, including a loss of normal regulation of endothelial cell degranulation as reflected by an increase in plasma von Willebrand factor and endothelial P-selectin expression. NO has an important role in regulating Weibel–Palade body exocytosis by S-nitrosylation of the key regulatory protein N-ethylmaleimide–sensitive factor (NSF).4,5 NO modification of NSF decreases NSF ATPase activity and, thus, blocks a critical function of NSF in promoting SNARE complex disassembly and sustaining exocytosis.4 Prdx1 / mice may therefore have an endothelial dysfunction by direct ROS effects or secondary to alterations in NO availability. A lack of proper ROS scavenging can lead to a decrease in bioavailable NO and perhaps unchecked exocytosis. ROS can decrease NO bioactivity by directly interacting with and inactivating NO or by modifying other protein sites where NO may react, therefore decreasing its physiological influence.3 With a loss of antioxidant activity, there may be a reduction in bioavailable NO, increased endothelial exocytosis, and, with it, increased P-selectin expression and von Willebrand factor release, such as in Prdx1 / mice. Increased endothelial exocytosis leads to increased WBC localization The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Md. Correspondence to Craig N. Morrell, The Johns Hopkins University School of Medicine, Broadway Research Building, Suite 853, Baltimore, MD 21205. E-mail [email protected] (Circ Res. 2008;103:571-572.) © 2008 American Heart Association, Inc.