Nitric Oxide and its Role in Cardiovascular Diseases (original) (raw)

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 .

The role of nitric oxide in cardiovascular diseases

Nitric oxide (NO) is a gaseous lipophilic free radical cellular messenger generated by three distinct isoforms of nitric oxide synthases (NOS), neuronal (nNOS), inducible (iNOS) and endothelial NOS (eNOS). NO plays an important role in the protection against the onset and progression of cardiovascular disease. Cardiovascular disease is associated with a number of different disorders including hypercholesterolaemia, hypertension and diabetes. The underlying pathology for most cardiovascular diseases is atherosclerosis, which is in turn associated with endothelial dysfunctional. The cardioprotective roles of NO include regulation of blood pressure and vascular tone, inhibition of platelet aggregation and leukocyte adhesion, and prevention smooth muscle cell proliferation.

Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis

Pharmacology & Therapeutics, 2005

Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. To date, 3 distinct NOS isoforms have been identified: neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3). Biochemically, NOS consists of a flavincontaining reductase domain, a heme-containing oxygenase domain, and regulatory sites. NOS catalyse an overall 5-electron oxidation of one N N -atom of the guanidino group of l-arginine to form NO and l-citrulline. NO exerts a plethora of biological effects in the cardiovascular system. The basal formation of NO in mitochondria by a mitochondrial NOS seems to be one of the main regulators of cellular respiration, mitochondrial transmembrane potential, and transmembrane proton gradient. This review focuses on recent advances in the understanding of the role of enzyme and enzyme-independent NO formation, regulation of NO bioactivity, new aspects of NO on cardiac function and morphology, and the clinical impact and perspectives of these recent advances in our knowledge on NO-related pathways. D

Nitric oxide and the endothelium: History and impact on cardiovascular disease

Vascular Pharmacology, 2006

There are few discoveries with the magnitude of the impact that NO has had on biology during the 25 years since its discovery. There is hardly a disease today not associated with altered NO homeostasis. In fact, despite numerous other endothelial functions, endothelial dysfunction has become synonymous with reduced biological activity of NO.

Nitric oxide synthases: regulation and function

2012

Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize L-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH 4). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin-and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.

Molecular control of nitric oxide synthases in the cardiovascular system

Cardiovascular Research, 1999

Nitric oxide plays an important role in cardiovascular homeostasis. In this review, the regulation of the three nitric oxide synthase isoforms in the cardiovascular system are examined at molecular and cellular levels. In addition, recent information gleaned from the use of NOS knockout mice are discussed.

The inducible nitric oxide synthase in vascular and cardiac tissue

European Journal of Pharmacology, 1999

Ž. Expression of the inducible form of nitric oxide synthase iNOS has been reported in a variety of cardiovascular diseases. The Ž. resulting high output nitric oxide NO formation, besides the level of iNOS expression, depends also on the expression of the metabolic pathways providing the enzyme with substrate and cofactor. NO may trigger short and long term effects which are either beneficial or Ž deleterious, depending on the molecular targets with which it interacts. These interactions are governed by local factors like the redox. state. In the cardiovascular system, the major targets involve not only guanylyl cyclase, but also other haem proteins, protein thiols, Ž. iron-non-haem complexes, and superoxide anion forming peroxynitrite. The latter has several intracellular targets and may be cytotoxic, despite the existence of endogenous defence mechanisms. These interactions may either trigger NO effects or represent releasable NO stores, able to buffer NO and prolong its effects in blood vessels and in the heart. Besides selectively inhibiting iNOS, a number of other Ž y. therapeutic strategies are conceivable to alleviate deleterious effects of excessive NO formation, including peroxynitrite ONOO scavenging and inhibition of metabolic pathways triggered by ONOO y. When available, these approaches might have the advantage to preserve beneficial effects of iNOS induction. Counteracting vascular hyper-responsiveness to endogenous vasoconstrictor agonists in septic shock, or inducing cardiac protection against ischaemia-reperfusion injury are examples of such beneficial effects of iNOS induction.

Nitric oxide in the cardiovascular system : a simple molecule with complex actions : review article

Cardiovascular Journal of Africa, 2009

Since it was identified as the elusive endothelium-derived relaxing factor (EDRF) in the 1980s, nitric oxide (NO) has rapidly gained status as one of the most important signalling molecules in the cardiovascular system. Now, 20 years later, NO is regarded by most to be a ubiquitous mediator of cardioprotection. However, due to various complex underlying cellular mechanisms, the actions of NO often seem to be contradictory. This article sheds light on some of the mechanisms that may influence the variable actions of NO in the heart.