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(Circulation Research. 2001;88:648.)
© 2001 American Heart Association, Inc.

Editorial

Reactive Oxygen Species and Death

Oxidative DNA Damage in Atherosclerosis

Martin R. Bennett

From Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, Cambridge, UK.

Correspondence to Martin R. Bennett, Addenbrooke’s Centre for Clinical Investigation, Box 110, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. E-mail mrb@mole.bio.cam.ac.uk

Key Words: p53 • reactive oxygen species • DNA repair

	Introduction

 
Reactive 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 LDL

 
Although 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 monocytes³ 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 DNA

 
ROS 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 (ATM-related 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 repair⁸ but also coordinates the cell’s response to damage. p53 phosphorylation stabilizes the protein and increases its transcriptional activity, inducing both . . . [Full Text of this Article]

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