Novel aspects of oxidative stress in cardiovascular diseases

Abstract

Oxygen radicals, and other reactive oxygen species, may play an important role in the pathophysiology of atherosclerosis, stroke, and other cardiovascular diseases. Mechanisms that account for oxidative stress in different cardiovascular diseases are diverse; for example, increases in activity of NAD(P)H oxidase, "uncoupling" of nitric oxide synthase, and maladaptive changes in expression of antioxidants can all contribute to increases in oxidative stress. Very different patterns of pro-and antioxidant mechanisms that contribute to increases in oxygen radicals in atherosclerotic plaques, hemorrhagic strokes, and aortic valve stenosis have been observed. A disappointment, in relation to the hypothesis that oxygen radicals contribute to cardiovascular risk, is that many studies indicate that antioxidant vitamins fail to reduce the risk of cardiovascular disease. Better understanding of mechanisms that lead to increases in oxidative stress in different cardiovascular diseases may lead to more effective antioxidant prevention or treatment of diseases.

Figure 1

Examples of diverse mechanisms by which oxidative stress may be increased in different tissues, with different consequences. In the aortic valve, oxidative tress appears to be produced by uncoupling of nitric oxide synthase (NOS) and reduction in antioxidant mechanisms (superoxide dismutases--SODs--and catalase). Oxidative stress in intracranial hemorrhage appears to be produced in part by increases in NAD(P)H oxidase activity. In arterial plaques, in coronary and other arteries, oxidative stress appears to be produced primarily by increases in NAD(P)H activity. Increases in superoxide (O₂.⁻) are augmented by a gene variant (ecSOD_R213G) that is common in humans.

Figure 2

In the aortic valve, superoxide appears to be generated by NOS (and perhaps other enzymes). Levels of superoxide are augmented by deficiency of SODs and catalase, and signaling cascades are activated that lead to fibrosis (primarily through TGFβ) and calcification of the valve (likely through TGFβ, CBFA1/Runx2, and Msx2).

Figure 3

The most frequently used model of intracranial hemorrhage (ICH) involves injection of blood or collagenase in the striatum. This approach is associated with increased NAD(P)H oxidase activity, reduction of SOD levels, and increased brain injury. We have developed two novel approaches to produce spontaneous ICH in hypertensive mice. NAD(P)H oxidase activity increases before and after spontaneous ICH, but it is not known whether SOD levels change. Oxidative stress activates matrix metalloproteinases (MMPs), and may contribute to both ICH and perhaps disruption of the blood-brain barrier (BBB).

Figure 4

As proposed initially by Oury and Crapo (36), ecSOD in blood vessels protects NO from inactivation by superoxide during diffusion from endothelium to smooth muscle cells. Impairment of binding of the ecSOD_R213G gene variant to vascular cells may lead to failure of this mechanism, increased oxidative stress in arteries, and is associated with increased risk of ischemic heart disease.