Regular paper
Role of oxidative stress in atherosclerosis

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Abstract

The common risk factors for atherosclerosis increase production of reactive oxygen species (ROS) by endothelial, vascular smooth muscle, and adventitial cells. These ROS initiate processes involved in atherogenesis through several important enzyme systems, including xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and nitric oxide synthase. Physical forces also regulate vascular production of ROS. Oscillatory shear, which is present at sites where atherosclerosis develops, seems a particularly potent stimulus of superoxide production. The signaling cascade for activation of the NAD(P)H oxidase by angiotensin II has recently been elucidated and seems to involve a feed-forward mechanism that permits ongoing production of ROS for prolonged periods. Oxidative stress in humans with coronary artery disease is also exacerbated by a reduction of vascular extracellular superoxide dismutase, normally an important protective enzyme against the superoxide anion.

Section snippets

Enzyme systems in the regulation of vascular oxidases

The NADPH oxidases have emerged as very important sources of ROS in vascular cells.4 An important aspect of this enzyme system is that it is regulated by a variety of pathophysiologic stimuli relevant to atherosclerosis, including angiotensin II, physical forces, and inflammatory cytokines. Recent work from Griendling et al4 has elucidated the signaling mechanism involved in angiotensin II activation of the NADPH oxidases.7 As shown schematically in Figure 3, it has been demonstrated at the

Physical forces in the regulation of vascular oxidases

In the 1980s, Ku et al12 demonstrated that oscillations of flow occur at sites in the circulation where atherosclerosis develops. In a model of the carotid bulb that allowed examination of flow profiles, these investigators demonstrated that there is reversal of flow with oscillations during systole. Such disturbances of flow profiles occur not only in the carotid bulb, but also in the abdominal aorta and the proximal coronary arteries, areas clearly predisposed to atherosclerosis.13 It has

Uncoupling of NOS

The NOSs, and in particular the endothelial isoform of NOS (eNOS), have emerged as important sources of superoxide in the last few years. These enzymes use 5,6,7,8-tetrahydrobiopterin (BH4) as a cofactor for transfer of electrons from a heme group within the oxygenase domain to l-arginine to form l-citrulline and NO. If either BH4 or l-arginine is absent, the electrons from heme reduce oxygen to form superoxide.15 In mice with deoxycorticosterone acetate salt hypertension, we have recently

Conclusions

Research from a number of laboratories has supported a role of ROS in the genesis of atherosclerosis, both in experimental animals and in humans. It is of interest that recent large trials have failed to show a benefit of antioxidant vitamins on cardiovascular outcome. We believe that future studies, should they be performed, should use antioxidants that are much more potent than the vitamins used in prior studies. Further, treatment of oxidative stress could be aided greatly by plasma or

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This work was supported by a grant from atherogenics, inc.

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