NO/redox disequilibrium in the failing heart and cardiovascular system

Abstract

There is growing evidence that the altered production and/or spatiotemporal distribution of reactive oxygen and nitrogen species creates oxidative and/or nitrosative stresses in the failing heart and vascular tree, which contribute to the abnormal cardiac and vascular phenotypes that characterize the failing cardiovascular system. These derangements at the integrated system level can be interpreted at the cellular and molecular levels in terms of adverse effects on signaling elements in the heart, vasculature, and blood that subserve cardiac and vascular homeostasis. Cellular damage versus malfunction in signalingAltered cellular production of ROS and/or reactive nitrogen species (RNS) is a ubiquitous feature of human disease. Many years of study, beginning with the discovery of superoxide (1) and superoxide dismutase (2), provide a sound understanding of the diverse chemical mechanisms by which these agents damage lipids, DNA, and proteins, and a pathophysiologic context is imparted by analyses of diseased tissues, which show the chemical footprints of oxidative and nitrosative stress (3-6). Thus, it has been widely assumed that direct chemical (oxidative and nitrosative) injury is a principal factor in the damage or disruption of cellular and subcellular structure-function that typifies such pathologic situations. A major difficulty with this hypothesis, however, lies in understanding how the salient features of chemical injury, which are common across organ systems, underlie the diverse pathophysiology of chronic disease. Moreover, irreversible oxidative damage cannot be easily reconciled with the acute restoration of cardiovascular performance by certain classes of antioxidants (see ref. 7 for example). It thus remains unclear to what extent the damage caused by RNS and ROS contributes to disease pathogenesis.It was appreciated early on that NO and/or related congeners have a function in signal transduction, and over the past decade, the idea that additional redox-active species may have signaling roles has been strengthened (8-13). Although the molecular mechanisms by which RNS and ROS modulate cellular signal transduction remain incompletely understood, there is a general consensus that cysteine residues are principal sites of redox regulation (10,13,14). Crosstalk between ROS-and RNS-regulated pathways may occur at both the chemical interaction level (15, 16) and through their coordinate effects on target proteins (17, 18); this is reflected in a growing awareness that RNS and ROS may subserve conjoint signaling roles. Analysis of several such examples (17)(18)(19)(20)(21)(22) has shown that S-nitrosylation (the covalent attachment of NO to cysteine thiol) may play a primary effector role while oxygen and other ROS may control the responsivity to S-nitrosylation (much as ROS control the strength of phosphorylation signaling by inhibiting phosphatases; ref. 11). This article addresses the physiologic and pathophysiologic consequences of the interplay between ROS and RNS in the cardiovascular system (Figure...

Compartmentalized Regulations of Ion Channels in the Heart

“…regulation of the channels is also through NO release through NOS3 activation. 63) Although there is evidence of direct s-nitrosylation of cardiac I Ca,L channels, 64,65) our results indicate differential mechanisms of the NO regulation through NOS3 between the I Ca,L channel and the I Ks channel, suggesting a compartmentalized regulation of I Ca,L and I Ks by NO. However, the mechanism for the compartmentalization of this NO regulation of cardiac ion channels has not been clarified.…”

Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery

“…The authors suggested that it may be that L-NMAE is transported into the cell using either diffusion or a transport system other than cationic amino acid transporter used by L-NMA [28,29]. In addition, NO is a part of the complex redox system that are known to be heavily involved in multiple cardiovascular signal transduction systems, which regulate contractility, blood flow, and heart rate [30][31][32]. Nevertheless, both inhibitors demonstrated similar results in this study and their effect on heart rate is minimal.…”

Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency

“…NO mediates a large number of physiological and pathophysiological effects via its cellular effector cGMP and cGMPindependent mechanisms (9). In dystrophin-deficient skeletal muscle, neuronal NO synthase (nNOS, one of the enzymes responsible for NO production) is displaced away from its normal subsarcolemmal location to the cytoplasm, where its mislocalization and decreased activity level are thought to contribute to muscle pathology (10)(11)(12)(13).…”