Nitric oxide and the resolution of inflammation: implications for atherosclerosis (original) (raw)
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Apoptosis and Atherosclerosis: The Role of Nitric Oxide
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2006
Atherosclerosis, and its associated complications, are a major cause of morbidity and mortality, and it is now recognised as a chronic inflammatory disorder. Progression of inflammation depends on the balance between recruitment of inflammatory cells and their subsequent removal from a site of inflammation. Apoptosis, or programmed cell death, is a fundamental process governing cell survival and is a major determinant of the resolution of the inflammatory response. Apoptotic cells are instantly recognised for non-inflammatory clearance by phagocytes (e.g. macrophages) and removed from the vicinity of inflammation without the release of their pro-inflammatory cell contents. Nitric oxide (NO) plays an important role in many biological processes and has several anti-atherogenic properties including vasodilatation, inhibition of platelet activation and aggregation, and the regulation of apoptosis in a variety of cell types involved in atherogenesis. A critical early event during atherog...
Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis
Cell Death & Differentiation, 2003
Apoptosis of inflammatory cells is a critical event in the resolution of inflammation, as failure to undergo this form of cell death leads to increased tissue damage and exacerbation of the inflammatory response. Many factors are able to influence the rate of apoptosis in neutrophils, eosinophils, monocytes and macrophages. Among these is the signalling molecule nitric oxide (NO), which possesses both anti-and proapoptotic properties, depending on the concentration and flux of NO, and also the source from which NO is derived. This review summarises the differential effects of NO on inflammatory cell apoptosis and outlines potential mechanisms that have been proposed to explain such actions.
Mechanisms of the pro- and anti-oxidant actions of nitric oxide in atherosclerosis
Cardiovascular Research, 2000
The association of nitric oxide (NO) with cardiovascular disease has long been recognized and the extensive research on this topic has revealed both pro-and anti-atherosclerotic effects. While these contradictory findings were initially perplexing recent studies offer molecular mechanisms for the integration of these data in the context of our current understanding of the biochemistry of NO. The essential findings are that the biochemical properties of NO allow its exploitation as both a cell signaling molecule, through its interaction with redox centers in heme proteins, and an extremely rapid reaction with other biologically relevant free radicals. The direct reaction of NO with free radicals can have either pro-or antioxidant effects. In the cell, antioxidant properties of NO can be greatly amplified by the activation of signal transduction pathways that lead to the increased synthesis of endogenous antioxidants or down regulate responses to pro-inflammatory stimuli. These findings will be discussed in the context of atherosclerosis.
The regulatory role of nitric oxide in apoptosis
International Immunopharmacology, 2001
Nitric oxide NO is a multi-faceted molecule with dichotomous regulatory roles in many areas of biology. The complexity of its biological effects is a consequence of its numerous potential interactions with other molecules such as Ž . reactive oxygen species ROS , metal ions, and proteins. The effects of NO are modulated by both direct and indirect interactions that can be dose-dependent and cell-type specific. For example, in some cell types NO can promote apoptosis, whereas in other cells NO inhibits apoptosis. In hepatocytes, NO can inhibit the main mediators of cell death-caspase proteases. Moreover, low physiological concentrations of NO can inhibit apoptosis, but higher concentrations of NO may be toxic. High NO concentrations lead to the formation of toxic reaction products like dinitrogen trioxide or peroxynitrite that induce cell death, if not by apoptosis, then by necrosis. Long-term exposure to nitric oxide in certain conditions like chronic inflammatory states may predispose cells to tumorigenesis through DNA damage, inhibition of DNA repair, alteration in programmed cell death, or activation of proliferative signaling pathways. Understanding the regulatory mechanisms of NO in apoptosis and carcinogenesis will provide important clues to the diagnosis and treatment of tissue damage and cancer. In this article we have reviewed recent discoveries in the regulatory role of NO in specific cell types, mechanisms of pro-apoptotic and anti-apoptotic induction by NO, and insights into the effects of NO on tumor biology. q 2001 Published by Elsevier Science B.V.
The role of nitric oxide in inflammatory reactions
FEMS Immunology & …, 2007
Nitric oxide (NO) was initially described as a physiological mediator of endothelial cell relaxation, an important role in hypotension. NO is an intercellular messenger that has been recognized as one of the most versatile players in the immune system. Cells of the innate immune system – macrophages, neutrophils and natural killer cells – use pattern recognition receptors to recognize the molecular patterns associated with pathogens. Activated macrophages then inhibit pathogen replication by releasing a variety of effector molecules, including NO. In addition to macrophages, a large number of other immune-system cells produce and respond to NO. Thus, NO is important as a toxic defense molecule against infectious organisms. It also regulates the functional activity, growth and death of many immune and inflammatory cell types including macrophages, T lymphocytes, antigen-presenting cells, mast cells, neutrophils and natural killer cells. However, the role of NO in nonspecific and specific immunity in vivo and in immunologically mediated diseases and inflammation is poorly understood. This Minireview will discuss the role of NO in immune response and inflammation, and its mechanisms of action in these processes.
Nitric oxide as a regulator of inflammatory processes
Nitric oxide (NO) plays an important role in mediating many aspects of inflammatory responses. NO is an effector molecule of cellular injury, and can act as an anti-oxidant. It can modulate the release of various inflammatory mediators from a wide range of cells participating in inflammatory responses (e.g., leukocytes, macrophages, mast cells, endothelial cells, and platelets). It can modulate blood flow, adhesion of leukocytes to the vascular endothelium and the activity of numerous enzymes, all of which can have an impact on inflammatory responses. In recent years, NO-releasing drugs have been developed, usually as derivatives of other drugs, which exhibit very powerful anti-inflammatory effects.
The Journal of Immunology, 2003
Treatment of the macrophage cell line RAW 264.7 with the short-lived NO donor S-nitrosoglutathione triggers apoptosis through the release of mitochondrial mediators. However, continuous supply of NO by long-lived NO donors protected cells from apoptosis through mechanisms that involved the maintenance or an increase in the levels of the inhibitor of apoptosis proteins (IAPs) cIAP-1, cIAP-2, and xIAP and decreases in the accumulation of p53 and in the levels and targeting of Bax to the mitochondria. As a result of these changes, the activation of caspases 9 and 3 was notably delayed, expanding the time of viability of the macrophages. Moreover, inhibition of NO synthase 2 activity after 8 h of stimulation of RAW 264.7 cells with LPS and IFN-γ accelerated apoptosis via an increase in the processing and activation of caspases. These data suggest that NO exerts an important role in the autoregulation of apoptosis in macrophages.
Cell signaling by reactive nitrogen and oxygen species in atherosclerosis
Free Radical Biology and Medicine, 2000
The production of reactive oxygen and nitrogen species has been implicated in atherosclerosis principally as means of damaging low-density lipoprotein that in turn initiates the accumulation of cholesterol in macrophages. The diversity of novel oxidative modifications to lipids and proteins recently identified in atherosclerotic lesions has revealed surprising complexity in the mechanisms of oxidative damage and their potential role in atherosclerosis. Oxidative or nitrosative stress does not completely consume intracellular antioxidants leading to cell death as previously thought. Rather, oxidative and nitrosative stress have a more subtle impact on the atherogenic process by modulating intracellular signaling pathways in vascular tissues to affect inflammatory cell adhesion, migration, proliferation, and differentiation. Furthermore, cellular responses can affect the production of nitric oxide, which in turn can strongly influence the nature of oxidative modifications occurring in atherosclerosis. The dynamic interactions between endogenous low concentrations of oxidants or reactive nitrogen species with intracellular signaling pathways may have a general role in processes affecting wound healing to apoptosis, which can provide novel insights into the pathogenesis of atherosclerosis.
Nitric oxide signalling in cardiovascular health and disease
Following the discovery of nitric oxide (NO) as one of the endothelium-derived relaxing factors (for which the Nobel Prize in Physiology or Medicine was awarded in 1998), a substantial body of evidence has confirmed the involvement of NO endogenously prod uced by the nitric oxide synthases (NOSs) in both the protection from and initiation of human vascular and cardiac disease. This apparent paradox stems from the more recently appreciated complexity of the distinctive regulation of NOS and NO bio availability. In particular, transcriptional and post-translational regulation of the NOSs and redox modulation of NOS and NO bio-activity, as well as of downstream elements of NO signalling (such as soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase (also known as protein kinase G; PKG)), dictate the final effect on target organs. The actions of NO are not limited to the control of cardiac or vascular contractility, but have been extended to the regulation of cardio vascular tissue remodelling (for example, fibrosis) and metabolism (such as in brown and perivascular fat). Intriguingly, NO can also be gener ated from nitrite and dietary nitrate through nitrate reductase expressed in com-mensal bacteria, further linking the microbiota to cardiovascular homeostasis. To untangle this complex regulation, we first review the distribution and molecular regulation of NOS isoforms in cardiovascular tissues as well as important elements of downstream NO signalling. We next summarize the latest experimental paradigms of NOS-mediated regulation of cardiac and vascular physiology. The following sections cover the mechanisms of dys-function of NOS signalling and the consequences of this dysfunction on cardiovascular pathophysiology. Finally, we focus on emerging paradigms in human diseases and review the latest developments in therapeutic strategies to modulate NO signalling. NOS isoforms in cardiovascular tissues NO is synthesized by three isoforms of NOS encoded by distinct genes: brain or neuronal NOS (nNOS; encoded by NOS1), inducible NOS (iNOS; encoded by NOS2), and endothelial NOS (eNOS; encoded by NOS3). The constitutively expressed nNOS and eNOS are highly regu lated by transcriptional, post-transcriptional (including microRNA), and post-translational mechanisms , including phosphorylation, acetyl ation, protein-protein interaction, S-nitrosylation, and S-gluta thio-nyl ation. Conversely, the inducible isoform, iNOS, is mainly regulated through gene transcription under pro-inflammatory and oxidative stress conditions. NOSs are oxidoreductase homodimer enzymes, composed of an amino-terminal oxygenase domain that contains binding sites for the substrate l-arginine, the cofactor tetrahydrobiopterin (BH 4), and a ferric haem cluster, as well as a reductase domain with binding sites for the electron donors nicotinamide adenine dinucleo-tide phosphate (NADPH), flavin adenine dinucleotide (FAD), and flavin mononucleotide (FMN). Both domains are connected by a sequence that binds calcium (Ca 2+)-complexed calmodulin. Upon NOS activation, the flavins in the reductase domain transfer NADPH-derived electrons to the haem in the oxygenase domain of the other mono mer, allowing oxygen (O 2) binding on the reduced haem iron (Fe 2+) and the conversion of l-arginine to HO-l-arginine, then NO and l-citrulline 1. Abstract | Nitric oxide (NO) signalling has pleiotropic roles in biology and a crucial function in cardiovascular homeostasis. Tremendous knowledge has been accumulated on the mechanisms of the nitric oxide synthase (NOS)-NO pathway, but how this highly reactive, free radical gas signals to specific targets for precise regulation of cardiovascular function remains the focus of much intense research. In this Review, we summarize the updated paradigms on NOS regulation, NO interaction with reactive oxidant species in specific subcellular compartments, and downstream effects of NO in target cardiovascular tissues, while emphasizing the latest developments of molecular tools and biomarkers to modulate and monitor NO production and bioavailability. NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 1 REVIEWS © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e. A l l r i g h t s r e s e r v e d .
Role of nitric oxide in inflammatory diseases
Inflammopharmacology, 2007
Nitric oxide (NO) is a signaling molecule that plays a key role in the pathogenesis of infl ammation. It gives an anti-infl ammatory effect under normal physiological conditions. On the other hand, NO is considered as a pro-infl ammatory mediator that induces infl ammation due to over production in abnormal situations. NO is synthesized and released into the endothelial cells by the help of NOSs that convert arginine into citrulline producing NO in the process. Oxygen and NADPH are necessary co-factors in such conversion. NO is believed to induce vasodilatation in cardiovascular system and furthermore, it involves in immune responses by cytokine-activated macrophages, which release NO in high concentrations. In addition, NO is a potent neurotransmitter at the neuron synapses and contributes to the regulation of apoptosis. NO is involved in the pathogenesis of infl ammatory disorders of the joint, gut and lungs. Therefore, NO inhibitors represent important therapeutic advance in the management of infl ammatory diseases. Selective NO biosynthesis inhibitors and synthetic arginine analogues are proved to be used for the treatment of NO-induced infl ammation. Finally, the undesired effects of NO are due to its impaired production, including in short: vasoconstriction, infl ammation and tissue damage.