Reactive Oxygen Species and Death

Abstract

R eactive oxygen species (ROS) (eg, superoxide, peroxide, and hydroxyl radicals) and reactive nitrogen species (eg, peroxynitrite) are generated in both atherogenesis and advanced atherosclerosis, 1 particularly by macrophages. 2 ROS have many actions, including oxidative modification of LDL and oxidative damage of DNA. Oxidative Modification of LDLAlthough LDL is essential to deliver cholesterol to tissues, increased LDL cholesterol is associated with increased risk of cardiovascular disease. Oxidative modification of LDL promotes recruitment and retention of monocytes 3 with formation of fatty streaks, the earliest lesions in atherosclerosis. 4 Both macrophages and vascular smooth muscle cells (VSMCs) bind oxidized LDL via specific scavenger receptors, 5,6 forming foam cells. Macrophage foam cells contain potent oxidant-generating systems that target lipids, including myeloperoxidase, nitric oxide (NO) synthase, and 15-lipoxygenase, allowing increased recognition and uptake by macrophages, creating a positive feedback loop. Oxidative Damage to DNAROS also induce oxidative damage of DNA, including strand breaks and base and nucleotide modifications, particularly in sequences with high guanosine content. 7 Oxidative modification induces a robust repair response, characterized by excision of modified bases and nucleotides. Double-stranded DNA breaks also activate DNA repair enzymes, including ATM (mutated in ataxia telangiectasia) and ATR (ATMrelated kinase). Both ATM and ATR directly phosphorylate and activate specific checkpoint kinases, such as chk2 and hCDS1, with subsequent phosphorylation of the tumor suppressor gene p53.p53 is the commonest mutation in human cancer and has a major role in genomic surveillance. p53 stimulates base excision repair 8 but also coordinates the cell's response to damage. p53 phosphorylation stabilizes the protein and increases its transcriptional activity, inducing both growth arrest and apoptosis. Thus, ROS-induced DNA damage leads to p53 activation, and growth arrest and apoptosis after DNA damage depend partly on p53.Although the presence of ROS within the atherosclerotic plaque is not disputed, the major target cells of ROS in vivo are unclear. In particular, ROS induce toxicity in many vascular cell types in culture. 9 In view of this, the study by Martinet et al 10 in this issue of Circulation Research provides important insights into the role of ROS in atherogenesis and plaque stability. These investigators demonstrated that cholesterol feeding of rabbits induces oxidative damage in plaques, manifested by expression of 8-oxo-G, an oxidative modification of guanine residues in DNA, 7 DNA strand breaks, and apoptosis. A graded response was seen, the percentage of cells expressing markers being 8-oxoGϾstrand breaksϾapoptosis, consistent with fewer cells demonstrating increasing degrees of oxidative damage. These changes were associated with expression of DNA repair enzymes and p53. Importantly, these markers of oxidative damage were rapidly reversible with cholesterol loweri...

Mediterranean diet supplemented with coenzyme Q10 induces postprandial changes in p53 in response to oxidative DNA damage in elderly subjects

“…However, few studies explored the effects that diet has on DNA damage during the postprandial state, or the effect of CoQ supplements in humans. Previous evidence showed that DNA damage plays a crucial role in the mechanisms of atherosclerosis (Bennett 2001), as well as other diseases related to aging. In the same line, studies carried out on rats fed with diets rich in polyunsaturated fatty acids demonstrated that CoQ supplements have a protective effect against oxidative damage (Thomas et al 1996;Santos-Gonzalez et al 2007).…”

PARP-1 Inhibition Prevents Oxidative and Nitrosative Stress–Induced Endothelial Cell Death via Transactivation of the VEGF Receptor 2

“…6 A major feature of atherosclerosis includes increased levels of reactive nitrosative species (RNS) and reactive oxygen species (ROS) associated with damage to cell membranes and DNA. 7,8 It is not surprising therefore that PARP-1 inhibition was also shown to limit endothelial dysfunction and atherosclerosis in the ApoE Ϫ/Ϫ mouse. 6,9 High levels of ROS and RNS, such as occur in ischemia-reperfusion injury, inflammation, and diabetes mellitus, induce DNA single-strand breaks and activate poly-ADP ribose polymerase-1 (PARP-1).…”

LOX-1 Receptor Blockade Abrogates oxLDL-induced Oxidative DNA Damage and Prevents Activation of the Transcriptional Repressor Oct-1 in Human Coronary Arterial Endothelium

“…There is also evidence for ROS to cause oxidative DNA damage in endothelium (11,12), which contributes to the pathogenesis of atherosclerosis and to instability of plaques (13)(14)(15). In patients with cardiovascular disease, the levels of oxLDL and circulating 8-hydroxy-2Ј-deoxyguanosine (8-OHdG) DNA-adducts correlate well (16).…”