This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

Role of Oxidative Modifications in Atherosclerosis

The generation of reactive oxygen species (ROS) and other free radicals (R) during metabolism is a necessary and normal process that ideally is compensated for by an elaborate endogenous antioxidant system. However, due to many environmental, lifestyle, and pathological situations, excess radicals can accumulate, resulting in oxidative stress. Oxidative stress has been related to cardiovascular disease, cancer, and other chronic diseases that account for a major portion of deaths today. Antioxidants are compounds that hinder the oxidative processes and thereby delay or prevent oxidative stress. This article examines the process of oxidative stress and the pathways by which it relates to many chronic diseases. We also discuss the role that endogenous and exogenous antioxidants may play in controlling oxidation and review the evidence of their roles in preventing disease.

Antioxidants and Prevention of Chronic Disease

Measurement of f(2)-isoprostanes as an index of oxidative stress in vivo

Oxidative stress has been associated with diverse pathophysiological events, including cancer, renal disease, and neurodegeneration. More recently, it has become apparent that reactive oxygen species (ROS) also play a role in the development of vasculopathies, including those that define atherosclerosis, hypertension, and restenosis after angioplasty. The “response to injury” hypothesis developed by Russell Ross in the late 1970s suggested that atherosclerosis, at least, resulted from an initial injury to endothelial cells, leading to impaired endothelial function and subsequent macrophage infiltration and smooth muscle dysfunction. Many investigators then focused on oxidation of LDL and its interaction with the endothelium as the initial injury leading to the formation of fatty streaks and ultimately atherogenesis. It is now clear not only that diverse ROS are produced in the vessel wall, but that they individually and in combination contribute to many of the abnormalities associated with vascular disease.

There are many ROS that play central roles in vascular physiology (Figure 1) and pathophysiology, the most important of which are nitric oxide (NO·), superoxide (O2·−), hydrogen peroxide (H2O2) and peroxynitrite (ONOO·−). NO· is normally produced by endothelial nitric oxide synthase (eNOS) in the vasculature, but in inflammatory states, inducible NOS can be expressed in macrophages and smooth muscle cells and contributes to NO·production. NO·is a crucial mediator of endothelium-dependent vasodilation and may also play a role in platelet aggregation and in maintaining the balance between smooth muscle cell growth and differentiation. Superoxide results from one electron reduction of oxygen by a variety of oxidases (Figure 2). When O2·− is produced in concert with NO·, they rapidly react to form the highly reactive molecule ONOO·−. ONOO·− is an important mediator of lipid peroxidation and protein nitration, including oxidation of LDL, which has dramatic proatherogenic effects. …

Oxidative Stress and Cardiovascular Injury Part I: Basic Mechanisms and In Vivo Monitoring of ROS

Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans

F2-Isoprostanes are prostaglandin (PG) isomers formed in situ in cell membranes by peroxidation of arachidonic acid. 8-epi PGF2alpha and IPF2alpha-I are F2-isoprostanes produced in humans which circulate in plasma and are excreted in urine. Measurement of F2-isoprostanes may offer a sensitive, specific, and noninvasive method for measuring oxidant stress in clinical settings where reactive oxygen species are putatively involved. We determined whether isoprostanes were present in human atherosclerotic lesions, where lipid peroxidation is thought to occur in vivo. 8-epi PGF2alpha ranged from 1.310-3.450 pmol/micromol phospholipid in atherectomy specimens compared with 0.045-0.115 pmol/micromol phospholipid (P < 0.001) in vascular tissue devoid of atherosclerosis. Corresponding values of IPF2alpha-I were 5.6-13.8 vs. 0.16-0.44 pmol/micromol phospholipid (P < 0.001). Levels of the two isoprostanes in vascular tissue were highly correlated (r = 0.80, P < 0.0001). Immunohistochemical studies confirmed that foam cells adjacent to the lipid necrotic core of the plaque were markedly positive for 8-epi PGF2alpha. These cells were also reactive with anti-CD68, an epitope specific for human monocyte/macrophages. 8-epi PGF2alpha immunoreactivity was also detected in cells positive for anti-alpha-smooth muscle actin antibody, which specifically recognizes vascular smooth muscle cells. Our results indicate that 8-epi PGF2alpha and IPF2alpha-I, two distinct F2-isoprostanes and markers of oxidative stress in vivo, are present in human atherosclerotic plaque. Quantitation of these chemically stable products of lipid peroxidation in target tissues, as well as in biological fluids, may aid in the rational development of antioxidant drugs in humans.

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J Rokach

Papers

Localization of distinct F2-isoprostanes in human atherosclerotic lesions.