nitric oxide signalling in cardiovascular health and disease pdf

Nitric Oxide Signalling In Cardiovascular Health And Disease Pdf

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This is an open access article distributed under the terms of Creative Commons Attribution License. Microorganisms and toxic factors are the predominant causative agents of periodontitis. In response to activated tissues, macrophages and lymphocytes produce matrix metalloproteinases and inflammatory factors, such as interleukin-1 IL-1 and tumor necrosis factor TNF 1 , which serve essential roles in periodontal tissue destruction.

Biological functions of nitric oxide

Victor W. Liu, Paul L. Nitric oxide NO is a gaseous molecule that plays many key roles in the cardiovascular system. Each of the enzymes that generate NO—neuronal, inducible and endothelial NO synthase—has been genetically disrupted in mice. This review discusses the cardiovascular phenotypes of each of the NO synthase NOS gene knockout mice, and the insights gained into the roles of NO in the cardiovascular system.

Mice lacking the endothelial isoform are hypertensive, have endothelial dysfunction and show a more severe outcome in response to vascular injury, to stroke and cerebral ischaemia, and to diet-induced atherosclerosis.

Mice lacking the neuronal isoform show a less severe outcome in response to stroke and cerebral ischaemia but have increased diet-induced atherosclerosis. Mice lacking the inducible isoform show reduced hypotension to septic shock.

Together, NOS gene knockout mice have been useful tools that complement our other approaches to studying the multiple roles of NO in the cardiovascular system. Nitric oxide NO is a key signaling messenger in the cardiovascular system. NO maintains vascular integrity by inhibiting platelet aggregation, 2 , 3 leukocyte—endothelium adhesion 4—6 and vascular smooth muscle proliferation.

The three NOS isoforms are encoded on separate chromosomes by separate genes. They share homology in regions involved in cofactor binding for example, FAD, FMN, and NADPH ribose and adenine binding sites , and have similar enzymatic mechanisms that involve electron transfer for oxidation of the terminal guanidino nitrogen of l -arginine.

However, their expression patterns differ, as do the detailed regulations of their activity. Despite their names, a variety of cell types express these isoforms, with many tissues expressing more than one isoform. In contrast, iNOS expression is induced in activated macrophages as an immune response.

For enzymatic activity, NOS proteins must bind cofactors and dimerize. Thus, the main switch for activity for nNOS and eNOS is a transient increase in intracellular calcium concentration, whereas the main switch for iNOS is at the level of transcription. Each isoform has notable structural features. However, whether mtNOS corresponds to one of the three known isoforms is not known. In many cells and for many of the biological signaling roles of NO, the physiologic target is soluble guanylate cyclase.

This is responsible for events in the brain following NMDA receptor activation. Garthwaite first described that cultures of cerebellar cells produce cGMP in response to the excitatory amino acid neurotransmitter glutamate.

Similarly, NO produced as a neurotransmitter in the autonomic nervous system innervating the gastrointestinal tract, urinary tract, and the respiratory tract, mediates smooth muscle relaxation in these tissues by increases in cGMP production. These effects are likely mediated by the phosphorylation of downstream proteins by cGMP-dependent protein kinases, including myosin light chain. Another target for NO is sulfhydryl groups on proteins, to form nitrosothiol compounds.

NOS enzymes can be inhibited by pharmacologic agents, including arginine analogs substituted at the terminal guanidino nitrogens. These arginine analogs bind to NOS, but cannot serve as substrate, so they compete with l -arginine and inhibit the enzyme. Such pharmacologic NOS inhibitors have yielded a tremendous amount of valuable information.

Indeed, blockade of a biological process by l -nitro-arginine L-NA or l - N -arginine-methyl-ester L-NAME , and outcompetition of this effect by an excess of l -arginine, provides very strong evidence for the involvement of NO in that process.

One potential limitation of pharmacologic inhibitors, however, is that they may inhibit more than one NOS isoform. There are also structurally distinct inhibitors of NOS that are not arginine analogs e. A complementary approach is to manipulate the genes that encode the NOS enzymes to generate knockout mice in which a particular NOS gene has been disrupted.

This approach complements pharmacologic approaches because its specificity is at the genetic level. Further, it allows the study of how chronic absence of the NOS isoform affects physiology in intact animals.

Several issues unique to the genetic approach should be kept in mind, as they can potentially confound studies using knockout animals. First, there may be developmental abnormalities due to the gene knockout.

If one of the NOS isoforms plays a critical role in embryonic development, its absence may lead to other secondary abnormalities that are difficult to predict. Second, additional phenotypes may emerge from changes to pathways that act upstream or downstream to the gene product of interest.

Third, other isoforms or gene products, acting in parallel, may compensate for the absent gene product and mask possible phenotypes. Finally, embryonic stem cells used to generate knockout mice are often derived from particular strains like the SV strain that are better sources of pluripotent embryonic stem cells. These knockout mice have mixed genetic background, which may itself lead to phenotypic abnormalities.

These splice variants are soluble, since they lack the PDZ domain. The most apparent phenotype of nNOS knockout mice is enlargement of the stomachs, often to several times the normal size, demonstrating a role for nNOS in smooth muscle relaxation of the pyloric sphincter. The first eNOS knockout mice were generated by disrupting the region that encodes for the NADPH ribose and adenine binding sites, which are essential for catalytic activity.

As outlined below, eNOS knockout mice show abnormalities in vascular relaxation, blood pressure regulation, and cardiac contractility. They are a useful animal model for endothelial dysfunction, as they show increased propensity to form neointima in response to vessel injury, 53 , 54 and accelerated and more severe diet-induced atherosclerosis in the apolipoprotein E apoE knockout mouse model.

Several additional strains of eNOS knockout mice have also been reported. In one strain, the eNOS gene was disrupted at the calmodulin binding site, encoded by exons 12 and 13, 57 In another strain, the NADPH ribose and adenine binding sites were disrupted, 58 similar to the first eNOS knockout mice. The fact that independently generated mice, particularly those in which different parts of the eNOS gene were targeted, have similar phenotypes, adds confidence that the observed phenotypes are specific.

Three separate groups independently disrupted the iNOS gene. MacMicking et al. None of the mutants demonstrate abnormalities in growth, fertility, or gross histopathology. Initial characterization of these iNOS mutant animals centered on two proposed functions of iNOS: cell-mediated resistance to pathogens, and hemodynamic responses to septic shock. Inducible NOS mutant mice are more sensitive to the intracellular pathogen Listeria monocytogenes 59 and to the intracellular protozoan parasite Leishmania major 60 than are wild-type mice.

Both are pathogens that elicit cell-mediated immune responses, and the increased susceptibility of iNOS mutant mice demonstrates the importance of iNOS to host defenses against these pathogens. The role of iNOS in septic shock is supported by the finding that NO is produced in large quantities during infection. In , Furchgott and Zawadzki found that acetylcholine is able to cause relaxation of blood vessels if, and only if, the endothelium is intact.

This indicated that acetylcholine does not act directly on vascular smooth muscle, but rather, that the endothelium plays a key role in vasodilation. This led to the proposal of the existence of endothelium-derived relaxing factor, or EDRF.

One of the first experiments in eNOS knockout mice was to replicate the experiments of Furchgott and Zawadzki. In fact, isolated aortic rings from eNOS knockout do not respond to acetylcholine in organ baths.

There are several interacting homeostatic regulators of blood pressure, including the renin—angiotensin system, the autonomic nervous system, and local mediators such as EDRF. L-NA and other NOS inhibitors cause a rise in blood pressure in many species, including rats, guinea pigs, rabbits, dogs and mice. Therefore, it was of particular interest to examine basal blood pressure in the eNOS mutant mice to see if other homeostatic mechanisms would compensate for the absence of endothelial NO production.

This is true regardless of the types of anesthesia used and in the awake state , and is also true for independently generated eNOS knockout mouse strains. Thus, eNOS plays a key role in regulation of blood pressure. However, it is not clear why other homeostatic systems cannot compensate for absence of eNOS.

The set point for systemic blood pressure is regulated through integration of cardiac, neuronal, humoral and vascular mechanisms.

One possibility is that the renin—angiotensin system and autonomic nervous system evolved to serve primarily as a defense against hypotension, and diminution in their activity is a poor buffer against hypertension. This hypotensive effect of L-NA is prevented by l -arginine and is not observed with d -nitro-arginine. This suggests that non-endothelial NOS isoforms may play a direct or indirect role in the maintenance of blood pressure.

Multiple roles for endothelial and non-endothelial NOS isoforms in vasodilation and vasoconstriction could also explain the observed variability in maximal pressor effects of various NOS inhibitors. NO is critical to the pathophysiology of vascular disease and the concept of endothelial dysfunction. Endothelial dysfunction is defined as impairment of physiologic endothelium-dependent relaxation. It occurs in atherosclerosis, hypertension, diabetes, hypercholesterolemia, and normal aging.

This is therefore an early event in the pathophysiology of atherosclerosis. Clinically, endothelial function can be tested by using ultrasound to determine the forearm blood flow response to reflow hyperemia.

Experimentally, endothelial function can be tested by using a myograph to determine the vasodilator response of an isolated vessel segment to pharmacologic agents such as acetylcholine, bradykinin, and VEGF. Endothelial dysfunction is characterized by diminished endothelial NO levels. Because eNOS knockout mice completely lack endothelial NO production, they serve as a model of extreme endothelial dysfunction.

Second, l -arginine, the substrate for NO production, can be limiting in tissues. An endogenous competitive inhibitor, asymmetric dimethylarginine ADMA may reduce endothelial NO production even in the presence of adequate l -arginine levels. Regulation of eNOS activity and mechanisms for endothelial dysfunction. While eNOS plays important roles in vessel function, excessive NO production may contribute to the development of atherosclerosis. NO and peroxynitrite can both increase oxidative stress and oxidize LDL.

NO can also affect redox-sensitive transcription of genes involved in endothelial cell activation such as VCAM Atherosclerosis is driven by biochemical, cellular, and hemodynamic forces in the vessel wall that cause vascular injury, ultimately leading to endothelial dysfunction, cellular proliferation, recruitment of inflammatory cells, and accumulation of oxidized LDL.

Vascular smooth muscle cells proliferate in the medial layer and migrate across the internal elastic lamina to form the neointima. NO suppresses smooth muscle proliferation in response to vessel injury, 91 suggesting that it normally serves a protective role. In association with other effects such as inhibition of platelet aggregation and adhesion 2 and inhibition of leukocyte activation and adhesion, 5 , 92 NO normally suppresses the processes that lead to the development of atherosclerotic plaques.

A relative deficiency in vascular NO would reduce these normally protective effects and thereby predispose to atherosclerosis. To assess whether eNOS has a role in neointima formation following vascular injury, eNOS knockout mice were subjected to a cuff model of vascular injury. Thus, results from eNOS knockout mice confirm results using pharmacologic agents, and show that a deficiency in the amount of available NO in the vessel wall by itself increases neointimal formation in response to vascular injury.

To mimic human diet-induced atherosclerosis, apoE knockout mice have been a useful mouse model. It is also the first murine model to demonstrate spontaneous distal coronary arteriosclerosis associated with left ventricular dysfunction.

These findings support the concept that restoration of eNOS function in patients with atherosclerosis is an important therapeutic goal. The reduction in atherosclerosis in double knockout animals is associated with decreased plasma levels of lipoperoxides, suggesting that reduction in iNOS-mediated oxidative stress may explain the protection from lesion formation in double knockout animals.

Thus, genetic deficiency of iNOS decreases atherosclerosis in Western diet-fed apoE knockout animals.

Redox Biology

Victor W. Liu, Paul L. Nitric oxide NO is a gaseous molecule that plays many key roles in the cardiovascular system. Each of the enzymes that generate NO—neuronal, inducible and endothelial NO synthase—has been genetically disrupted in mice. This review discusses the cardiovascular phenotypes of each of the NO synthase NOS gene knockout mice, and the insights gained into the roles of NO in the cardiovascular system.

Part of the Nutrition and Health book series NH. Skip to main content Skip to table of contents. Advertisement Hide. This service is more advanced with JavaScript available. Nitrite and Nitrate in Human Health and Disease. Editors view affiliations Nathan S.

The initial identification of NO as an endothelium-derived relaxing factor EDRF [ 3 ] generated great interest in its function in vascular biology. Over the following years, however, the focus on NO research rapidly expanded from the vascular system to its role in immunity and inflammation, the nervous system, pregnancy, aging, and cell death. The aim of this Special Issue is to gather information encapsulating the above signalling pathways. The articles published in this Special Issue largely cover 1 NO signalling in neuronal function and disease as well as 2 vascular targets in endothelial function and dysfunction, both of which involve the broad range of actions of this signalling molecule. In order to understand the contribution of NO to neuronal dysfunction, one has to consider that NO is a crucial molecule in cellular physiology. Numerous studies show the involvement of NO in neuronal development, plasticity, excitability, and transmission [ 8 — 12 ].

Nitric Oxide Signalling in Vascular Control and Cardiovascular Risk

Nitric Oxide NO is an essential signaling molecule with diverse physiological functions in humans. The steady-state concentration and site of production of nitric oxide determine its effects in biological systems. The human cells are exposed to both beneficial and harmful effects of NO. These dual effects of NO could depend on its local concentration in the cells.

Nitric oxide nitrogen monoxide is a molecule and chemical compound with chemical formula of N O. In mammals including humans, nitric oxide is a signaling molecule involved in many physiological and pathological processes. Standard pharmaceuticals such as nitroglycerine and amyl nitrite are precursors to nitric oxide. Low levels of nitric oxide production are typically due to ischemic damage in the liver. As a consequence of its importance in neuroscience , physiology , and immunology , nitric oxide was proclaimed " Molecule of the Year " in

Cardiovascular Risk Factors. Nitric oxide — a free radical molecule — has been known for many decades, but only since its recognition as endothelium-derived relaxing factor EDRF the interest in the molecule has exponentially increased Moncada, Three isoforms of NOS have been identified. As major signalling molecule of the vascular system NO is generated by the constitutively expressed eNOS. The endothelium maintains the balance between vasodilation and vasoconstriction.

Nitric oxide signalling in cardiovascular health and disease

Table of contents

КЛУШАР - ЛИКВИДИРОВАН Он улыбнулся. Часть задания заключалась в немедленном уведомлении. Но сообщать имена жертв… с точки зрения человека в очках в металлической оправе, это было признаком особой элегантности стиля. Его пальцы снова задвигались, приводя в действие сотовый модем, и перед глазами появилось: СООБЩЕНИЕ ОТПРАВЛЕНО ГЛАВА 26 Сидя на скамейке напротив городской больницы, Беккер думал о том, что делать. Звонки в агентства услуг сопровождения ничего не дали. Коммандер, недовольный необходимостью говорить по линии, не защищенной от прослушивания, попросил Дэвида не звонить, пока кольцо не окажется в его руках.

Он и так скоро уйдет. Код, не поддающийся взлому. Сьюзан вздохнула, мысли ее вернулись к Цифровой крепости. Она не могла поверить, что такой алгоритм может быть создан, но ведь доказательство налицо - у нее перед глазами.

Мое тело мне больше не принадлежит. И все же он слышал чей-то голос, зовущий. Тихий, едва различимый. Но этот голос был частью его .

 - Она застонала. Все четко, ясно и. Танкадо зашифровал Цифровую крепость, и только ему известен ключ, способный ее открыть.

Энсей пользовался всеобщим уважением, работал творчески, с блеском, что дано немногим. Он был добрым и честным, выдержанным и безукоризненным в общении. Самым главным для него была моральная чистота.

Агенты сейчас будут. Сьюзан попробовала выскользнуть из его рук, Хейл очнулся и притянул ее к себе за талию. - Отпусти меня! - крикнула она, и ее голос эхом разнесся под куполом шифровалки.


Tyler B.

Nitric oxide (NO) signalling has pleiotropic roles in biology and a crucial function in cardiovascular homeostasis. In this Review, Balligand and.


Ganix C.

To read the full-text of this research, you can request a copy directly from the authors. Request full-text PDF.


Claus Z.

Regulation of endothelial derived nitric oxide in health and disease.


Claribel G.

Nitric oxide (NO) signalling has pleiotropic roles in biology and a crucial function in cardiovascular homeostasis. Tremendous knowledge has.


Corette R.

Abstract: Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. NO is a free have many opposing roles in cell signalling and vascular Giles, T. D. Aspects of nitric oxide in health and disease: a focus.


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