6533b7d9fe1ef96bd126d50c

RESEARCH PRODUCT

Uncoupling of Endothelial Nitric Oxide Synthase in Cardiovascular Disease and its Pharmacological Reversal

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Publisher Summary This chapter discusses the role of oxidative stress in vascular dysfunction and atherogenesis, and strategies for its prevention. Endothelial dysfunction and oxidative stress have been identified as a common denominator of many cardiovascular risk factors. They support pro-inflammatory, prothrombotic, proliferative, and vasoconstrictor mechanisms that are involved in the initiation, progression, and complications of atherosclerosis. The pathophysiologic causes of oxidative stress involve changes in a number of different enzyme systems. Increased production of ROS by uncoupled eNOS is likely to contribute significantly to vascular oxidative stress and endothelial dysfunction. Endothelium-derived nitric oxide (NO) is an antithrombotic and anti-atherosclerotic factor because it dilates blood vessels, inhibits platelet function, prevents adhesion of leukocytes to the vascular wall, and limits proliferation of vascular smooth muscle cells. Endothelial dysfunction characterized by enhanced inactivation and/or reduced synthesis of NO is seen in conjunction with risk factors for cardiovascular disease. Endothelial dysfunction can promote vasospasm, thrombosis, vascular inflammation, and proliferation of the intima. Vascular oxidative stress, i.e., an increased production of reactive oxygen species, represents a major cause of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes such as NADPH oxidase, xanthine oxidase, or the mitochondrial respiratory chain and anti-oxidative enzymes such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase, and paraoxonase in favor of the former. Increased reactive oxygen species concentrations reduce bioactive NO by chemical inactivation to form toxic peroxynitrite. Peroxynitrite in turn can “uncouple” endothelial NO synthase to become a dysfunctional superoxide-generating enzyme that contributes to vascular oxidative stress.