Nitroso–Redox Interactions in the Cardiovascular System

Abstract

cardiovascular performance requires exquisite balancing of many complex biochemical processes.Perturbation of this balance may lead to myocardial dysfunction or may be a secondary result of structural heart disease such as myocardial infarction (MI) or cardiomyopathic processes.Altered signaling systems in turn contribute to the progression of myocardial dysfunction.The roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in normal and failing myocardium and vasculature have been the subject of intense investigation and continue to engender considerable debate.A disturbance in the oxidation-reduction state of the cell, in which ROS production exceeds antioxidant defenses, is called oxidative stress.By analogy, nitrosative stress is an impairment in nitric oxide (NO) signaling caused by increased amounts of RNS, which may be caused by or associated with a disturbance in the redox state.This review addresses the role of the redox state and nitroso-redox balance in determining cardiovascular function in health and disease. The Chemistry of Nitroso-Redox BalanceFree radicals are highly reactive molecules with unpaired electrons.Free radical chemistry is the underpinning of 2 broad classes of signaling molecules in biological systems: ROS, which are reactive intermediates of oxygen metabolism, and a closely related group of RNS.The forms of ROS that are relevant in biological systems include the superoxide radical (O 2 •Ϫ ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical (OH • ). 1 RNS of biological importance include NO, lowand high-molecular-weight S-nitrosothiols, and peroxynitrite (ONOO Ϫ ) 2 (Figure 1). Superoxide, Peroxide, and PeroxynitriteSuperoxide is formed by the 1-electron reduction of molecular oxygen, resulting in a free radical.3 This reductive process can be accomplished by a variety of oxidases, including xanthine oxidase (XO) and NADPH oxidases, or as a byproduct of oxidative phosphorylation.XO produces varying proportions of superoxide and hydrogen peroxide during reoxidation of the enzyme 4 (Figure 2).Peroxynitrite (ONOO Ϫ ) is a product of the reaction of NO with superoxide.At physiological pH, ONOO Ϫ is protonated to form peroxynitrous acid, which is a highly reactive species with a very short half-life in vivo.ONOO Ϫ is able to react with DNA, proteins, and lipids, potentially leading to cellular damage and cytotoxicity.ONOO Ϫ reaction with CO 2 is a physiologically relevant pathway, given the high rate constant for this reaction and the relatively high concentration of CO 2 in vivo.5 This reaction forms intermediates that provide a route to nitration and oxidation.Tyrosine nitration by ONOO Ϫ has been demonstrated in vitro and has long been suspected as a mechanism of protein inactivation.6,7 However, the mechanisms of protein inactivation by ONOO Ϫ are multifactorial and nonspecific with multiple targets, including thiols, methionine, and amines.8 In the case of the sarcoplasmic reticulum (SR) calcium ATPase (SERCA), for example, oxidation at multiple cysteine residues leads to loss of function.9 Biochemistry of Nitroso-Redox ROS and RNS as Second MessengersA key concept in understanding redox balance in the cardiovascular system is that the effects of ROS and RNS depend on the location, amount, and timing of their production.22 ROS are not intrinsically destructive; on the contrary, increasing