Delivery of oxygen to tissues is the primary function of the cardiovascular system. NO, a gasotransmitter that signals predominantly through protein S-nitrosylation to form S-nitrosothiols (SNOs) in target proteins, operates coordinately with oxygen in mammalian cellular systems. From this perspective, SNO-based signaling may have evolved as a major transducer of the cellular oxygen-sensing machinery that underlies global cardiovascular function. Here we review mechanisms that regulate S-nitrosylation in the context of its essential role in "systems-level" control of oxygen sensing, delivery, and utilization in the cardiovascular system, and we highlight examples of aberrant S-nitrosylation that may lead to altered oxygen homeostasis in cardiovascular diseases. Thus, through a bird's-eye view of S-nitrosylation in the cardiovascular system, we provide a conceptual framework that may be broadly applicable to the functioning of other cellular systems and physiological processes and that illuminates new therapeutic promise in cardiovascular medicine.
"The initial discovery by Murad in 1977 that exogenous NO can act as a bioactive messenger to activate soluble guanylate cyclase (sGC) in SMCs (Katsuki et al., 1977), along with the work by Furchgott and Zawadzki (1980) identifying the presence of an endothelium derived relaxing factor that has since been identified as NO (Ignarro et al., 1987; Palmer et al., 1987), fueled the concept that NO is an essential player in regulating blood vessel physiology. Since then, a number of intra-and intercellular targets for bioactive NO have been identified with the biological effects ranging from enzyme activation or inhibition, posttranslational modifications altering protein function, including S-nitrosylation and tyrosine nitrosation, and the generation of complex reactive nitrogen and oxygen species through the rapid spontaneous reaction of NO with other gaseous molecules in the cell (Ignarro, 1991; Davidge et al., 1995; Xu et al., 1998; Handy and Loscalzo, 2006; Yoshida et al., 2006; Kang-Decker et al., 2007; Selemidis et al., 2007; Zuckerbraun et al., 2007; Illi et al., 2008; Briones et al., 2009; Fernhoff et al., 2009; Lima et al., 2010; Thibeault et al., 2010; Bess et al., 2011; Choi et al., 2011; Straub et al., 2011; Marin et al., 2012; Haldar and Stamler, 2013; Korkmaz et al., 2013). It has now become evident that the spatial and temporal regulation of reactive nitrogen and oxygen species generation can dictate the functional impact of these signaling molecules on the homeostatic maintenance of vascular function, where dysregulation can lead to complications including, but not limited to, endothelial dysfunction, inflammation, and atherosclerosis (reviewed by Giles, 2006; Pacher et al., 2007; Muller and Morawietz, 2009). "
[Show abstract][Hide abstract] ABSTRACT: It has become increasingly clear that the accumulation of proteins in specific regions of the plasma membrane can facilitate cellular communication. These regions, termed signaling microdomains, are found throughout the blood vessel wall where cellular communication, both within and between cell types, must be tightly regulated to maintain proper vascular function. We will define a cellular signaling microdomain and apply this definition to the plethora of means by which cellular communication has been hypothesized to occur in the blood vessel wall. To that end, we make a case for three broad areas of cellular communication where signaling microdomains could play an important role: 1) paracrine release of free radicals and gaseous molecules such as nitric oxide and reactive oxygen species; 2) role of ion channels including gap junctions and potassium channels, especially those associated with the endothelium-derived hyperpolarization mediated signaling, and lastly, 3) mechanism of exocytosis that has considerable oversight by signaling microdomains, especially those associated with the release of von Willebrand factor. When summed, we believe that it is clear that the organization and regulation of signaling microdomains is an essential component to vessel wall function.
"These effects can occur either as direct actions of CO, or (and more commonly) CO effects on closely related intracellular signaling pathways, often involving nitric oxide signaling, metabolism, and/or downstream targets for chemical modifications of individual amino acids in functional proteins. In the cardiovascular system, specific attention has been drawn to S-nitrosylation of, specific ion channel residues (Jaffrey et al., 2001; Haldar and Stamler, 2013). "
[Show abstract][Hide abstract] ABSTRACT: Carbon monoxide (CO) that is produced in a number of different mammalian tissues is now known to have significant effects on the cardiovascular system. These include: (i) vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation of autonomic nervous system input to both the primary pacemaker and the working myocardium. Excessive CO in the environment is toxic and can initiate or mediate life threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias to an increase in the slowly inactivating, or "late" component of the Na(+) current in the mammalian heart. The main goal of this paper is to explore the basis of this pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel activity with intracellular signaling pathways in the mammalian heart. To do this, a quite well-documented mathematical model of the action potential and intracellular calcium transient in the human ventricular myocyte has been employed. In silico iterations based on this model provide a useful first step in illustrating the cellular electrophysiological consequences of CO that have been reported from mammalian heart experiments. Specifically, when the Grandi et al. model of the human ventricular action potential is utilized, and after the Na(+) and Ca(2+) currents in a single myocyte are modified based on the experimental literature, early after-depolarization (EAD) rhythm disturbances appear, and important elements of the underlying causes of these EADs are revealed/illustrated. Our modified mathematical model of the human ventricular action potential also provides a convenient digital platform for designing future experimental work and relating these changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data on CO toxicity.
Frontiers in Physiology 10/2013; 4:282. DOI:10.3389/fphys.2013.00282 · 3.53 Impact Factor
"As a classical intracellular signaling cascade, the NO–cGMP–PKG signaling pathway has been extensively documented for its effects on proteins phosphorylation (Coletta et al., 2012). Nevertheless, recent studies have demonstrated that a large part of NO's ubiquitous influence is exerted through the S-nitrosylation of protein thiols (Hess et al., 2005; Aranda et al., 2012; Pan et al., 2008; Haldar and Stamler, 2013). This reversible post-translational modification performs an important mechanism in apoptosis, ion channel activation and mitochondrial caspases regulation by increasing or inhibiting enzyme activity. "
[Show abstract][Hide abstract] ABSTRACT: The high-level production of nitric oxide (NO) induced by inflammatory cytokines has been shown to play a key role in the pathogenesis of inflammation-mediated osteoporosis. In the present work, we observed that 1mM of the NO donor sodium nitroprusside (SNP) induced an increase of the cytosolic calcium concentration ([Ca(2+)]c) in osteoblasts, which was completely abolished by applying an extracellular Ca(2+)-free buffer. Further experiments showed that the SNP-induced [Ca(2+)]c increase was specifically blocked by potent antagonists of the transient receptor potential vanilloid subtype 1 (TRPV1) channel: capsazepine, ruthenium red, and La(3+) in Ca(2+)-containing buffer, respectively. However, nifedipine, an L-type voltage sensitive Ca(2+)-channel blocker, failed to suppress the [Ca(2+)]c elevation caused by SNP. Additionally, 1mM SNP induced osteoblast apoptosis, which was largely inhibited by the blockers of TRPV1, capsazepine and ruthenium red. Interestingly, our data showed that the SNP-induced [Ca(2+)]c increase was significantly inhibited by N-ethylmaleimide, the blocker of S-nitrosylation modification, instead of inhibitors of the NO-cGMP-PKG pathway. Taken together, our data clearly demonstrated that the NO donor SNP resulted in apoptosis associated with TRPV1 channel-mediated Ca(2+) entry via S-nitrosylation in osteoblasts.
European journal of pharmacology 05/2013; 715(1). DOI:10.1016/j.ejphar.2013.05.009 · 2.53 Impact Factor
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