Reactive Oxygen Species as Mediators of Signal Transduction in Cardiovascular Disease

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Abstract

Reduction-oxidation (redox) reactions that generate reactive oxygen species (ROS) have been identified as important chemical processes that regulate signal transduction. Because increased ROS may be a risk factor for cardiovascular events such as unstable angina, myocardial infarction and sudden death, understanding the biological processes that generate ROS and the intracellular signals elicited by ROS will be important to gain insight into the pathogenesis of these diseases. In this review, we discuss the enzymes that generate ROS in cardiovascular tissues, the role of the mitogen-activated protein (MAP) kinase pathway in redox-sensitive signal transduction, and focus on tyrosine kinases as proximate “sensors” for redox-mediated signal events. The mechanisms by which these kinases regulate gene transcription are then discussed to provide insight into the pathogenic roles of ROS in hypertension, atherosclerosis and vascular remodeling.

Section snippets

• What Are Reactive Oxygen Species and Where Do They Come From?

ROS include both free radicals, which typically have an oxygen- or nitrogen-based unpaired electron, and other species, such as H2O2, that act as oxidants. Classic examples of free radicals are O2 (superoxide anion), ·OH (hydroxyl radical) and ·NO (nitric oxide). There are several pathways in aerobic cells that produce oxygen-derived ROS (Fig. 1). Mitochondria, endoplasmic reticulum, and nuclear membranes have been shown to produce superoxide as a consequence of oxidative phosphorylation.

• Reactive Oxygen Species as Inducers of NF-κB and AP-1 Activation

NF-κB is an inducible transcription activator that is a likely target for ROS signal transduction. NF-κB is a heterodomer containing a 50- and a 65-kD subunit (termed p50 and p65). There are two forms of NF-κB in the cell, an inactive form in the cytosol and an active form in the nucleus. Cytosolic NF-κB activation can be brought about by a variety of stimuli including cytokines, physical stress such as UV and ionizing radiation, and oxidants such as H2O2. Activation of NF-κB by ROS may be

• Reactive Oxygen Species and the Cardiovascular System in Pathologic Process

Three cardiovascular processes in which ROS are likely to play a pathogenic role are hypertension, atherosclerosis, and vascular remodeling. Links between oxidative stress and hypertension have been established recently with the demonstration that angiotensin II increases production of ROS by VSMC (Griendling et al. 1994). Recently, it was shown that angiotensin II-induced hypertension was associated with increased vascular O2 production and that treatment with liposome-encapsulated superoxide

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