The role of nitric oxide in cardiovascular diseases

doi:10.1016/j.mam.2004.09.003

Molecular Aspects of Medicine

Volume 26, Issues 1–2, February–April 2005, Pages 33-65

https://doi.org/10.1016/j.mam.2004.09.003 Get rights and content

Abstract

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.

Reduced bioavailability of NO is thought to be one of the central factors common to cardiovascular disease, although it is unclear whether this is a cause of, or result of, endothelial dysfunction. Disturbances in NO bioavailability leads to a loss of the cardio protective actions and in some case may even increase disease progression. In this chapter the cellular and biochemical mechanisms leading to reduced NO bioavailability are discussed and evidence for the prevalence of these mechanisms in cardiovascular disease evaluated.

Introduction

Cardiovascular disease (CVD) is most common among populations of the industrialised countries, where standards of living are high. CVD is also one of the main causes of death globally. Within Europe, the UK has one of the worst records of cardiovascular disease, particularly in Scotland and Northern Ireland. This may be associated with the distribution of social class groups in these regions. It is rising in countries of the Indian sub-continent. In Japan, the levels of CVD are low, but may rise with increased westernisation. In the USA, Western Europe, the deaths from CVD are falling, but the number of individuals with symptoms is not following this trend and many lives are being saved by the availability of new drugs such as the statins. The death rate from CVD is increasing rapidly in Eastern Europe.

Cardiovascular disease encompasses a number of different diseases including coronary heart disease, stroke and peripheral vascular disease. However, the underlying pathology for all of these disorders is atherosclerosis. The pathology of atherosclerosis is extremely complex and involves all the structural elements of the arterial wall, circulating cells such as platelets and leukocytes and a number of inflammatory cells particularly monocytes/macrophages (see Fig. 1). Central to the process is the vascular endothelium, which acts as a dynamic interface between the circulation and the arterial wall. Changes in the artery wall occur throughout life, but atherosclerosis is a pathological process that is different from ageing. It may even begin in childhood and is certainly present in many teenagers in the most industrialised countries. In itself, it is not usually life-threatening until the later stages, but many are struck down in middle age.

It is important to understand the pathogenesis of the atherosclerosis. A brief overview of the pathobiology of atherosclerosis is provided here: for more in depth material the reader is directed to an excellent review (Lusis, 2000).

Section snippets

The pathobiology of atherosclerosis

There are several clear phases in the development of atherosclerotic plaque which only in a minority of cases proceed to the final or thrombotic phase which normally is associated with myocardial infraction. The phases are as follows.

Lipoprotein oxidation

A central factor in the aetiology of atherosclerosis is the cholesterol-rich fraction of the blood, the low-density lipoproteins (LDL). LDL diffuse passively into the arterial wall and become trapped through an interaction between its protein moiety, apolipoprotein B₁₀₀ and matrix proteoglycans. In the subendothelium, LDL becomes oxidatively modified from prolonged exposure to reactive oxygen and nitrogen species (ROS and RNS). These are generated by vascular cells, particularly by

The protective properties of nitric oxide

The cells of the vascular endothelium transduce circulatory stimuli to the arterial wall leading to the regulation of vessel tone, haemostasis, blood pressure and vascular remodelling. It is the ability of the endothelium to synthesise and release NO that accounts for the regulation of these physiological processes. Atherosclerosis, and diseases which predispose to atherosclerosis such as hypercholesterolaemia, diabetes, and hypertension, are characterised by endothelial dysfunction. Here

Factors that affect the bioavailability of nitric oxide in the cardiovascular system

The reduced bioavailability of NO is thought to be one of the central factors common to vascular disease, although it is unclear whether this is a cause of, or result of, endothelial dysfunction. There are a number of factors which could potentially affect either the production of NO, or the ability of NO to diffuse to its cellular targets. Disturbances in NO bioavailability lead to altered regulation of key physiological and cellular processes such as vasodilatation, platelet function,

Nitric oxide and cardiovascular disease

The dysregulation of NO metabolism as a contributing factor has been demonstrated in a number of vascular pathologies including atherosclerosis, hypercholesterolaemia, diabetes, hypertension and septic shock. The common factor is endothelial dysfunction in which an alteration in NO bioavailability is likely to play an important role. In the following section the role of NO in each of these diseases will be explored.

Diabetes and nitric oxide

Diabetes mellitus is associated with increased rates of morbidity and mortality caused primarily by the accelerated development of atherosclerotic disease (Beckman et al., 2002). Similar to other atherosclerotic pathologies diabetic vascular disease is characterised by endothelial dysfunction. Human IDDM and NIDDM, and animal models of IDDM are all associated with a reduced endothelium-dependent relaxation, although the response to exogenous NO-donors is often normal (Durante et al., 1988;

Nitric oxide and hypertension

NO is crucial to the maintenance of normal blood pressure (Huang et al., 1995) and therefore its relationship to essential hypertension has been the subject of intense investigation. As with coronary artery disease and diabetes initial evidence suggesting a NO-dependent component of the disease came from studies assessing endothelium-dependent vasodilatation. A number of studies have demonstrated the impairment of NO-mediated vasodilatation in brachial (Panza et al., 1995), coronary (Treasure

The importance of platelet nitric oxide production

The previous sections have concentrated on endothelial-derived NO, however the importance of platelet-derived NO in vascular disease is now recognised. In contrast, to the basal release of endothelial NO, platelet-derived NO is released in response to cell activation: it is very localised and is released specifically to attenuate thrombosis. NO released by activated platelets in vitro markedly inhibits the secondary recruitment of platelets into aggregates, consistent with a role limiting

Nitric oxide and septic shock

This review has concentrated on vascular diseases, which are associated with reduced bioavailability of NO, however septic shock represents a disorder in which overproduction of NO is critical. Septic shock has a mortality rate of up to 60% and is characterised by hypotension, compromised vascular function and multi-organ failure. The hypotension associated with septic shock is brought about by a massive increase in NO production, emanating primarily from NOSII present in VSMC.

Concluding remarks

The aim of the review was to provide the reader with an overview of what is an enormous and extremely vigorous area of biomedical research. NO has emerged as a prominent protector against cardiovascular disease. The consensus suggests that the level of NO synthesis does not change dramatically with disease. However, the increased oxidative stress associated with cardiovascular pathologies has the potential to shift the balance from NO being a protective to an injurious agent. Therapeutic

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ReviewThe role of nitric oxide in cardiovascular diseases

Abstract

Introduction

Section snippets

The pathobiology of atherosclerosis

Lipoprotein oxidation

The protective properties of nitric oxide

Factors that affect the bioavailability of nitric oxide in the cardiovascular system

Nitric oxide and cardiovascular disease

Diabetes and nitric oxide

Nitric oxide and hypertension

The importance of platelet nitric oxide production

Nitric oxide and septic shock

Concluding remarks

Atherosclerosis

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Am. J. Hypertens.

Nutrition

Trends Mol. Med.

Eur. J. Pharmacol.

Am. J. Cardiol.

Eur. J. Pharmacol.

FEBS Lett.

J. Am. Coll. Cardiol.

Kidney Int.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

FEBS Lett.

Am. J. Cardiol.

Cell

J. Biol. Chem.

Effects of chronic diabetes on vascular responses of basilar artery and aorta from rabbits with alloxan-induced diabetes

Res. Commun. Chem. Pathol. Pharmacol.

Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase

Arterioscler. Thromb. Vasc. Biol.

Inhibition of proliferation, but not of Ca2+ mobilization, by cyclic AMP and GMP in rabbit aortic smooth-muscle cells

Biochem. J.

Role of nitric oxide in the angiogenic response in vitro to basic fibroblast growth factor

Circ. Res.

Diabetes and atherosclerosis: epidemiology, pathophysiology, and management

JAMA

Nitric oxide, superoxide and peroxynitrite: the good, the bad, and the ugly

Am. J. Physiol.

Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry

Biol. Chem. Hoppe Seyler

Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease

Circulation

p53 accumulation in apoptotic macrophages is an energy demanding process that precedes cytochrome c release in response to nitric oxide

Oncogene

Effect of local intra-arterial NG-mono-methyl-l-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal

J. Hypertens.

Oxidative modification of low density lipoprotein (LDL) by activated human monocytes and the cell lines U937 and HL60

In Vitro Cell Dev. Biol.

Detection of nitrotyrosine in the diabetic plasma: evidence of oxidative stress

Diabetologia

Lack of effect of vitamin E on l-arginine-responsive endothelial dysfunction in patients with mild hypercholesterolaemia and coronary artery disease

Clin. Sci. (Lond.)

Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta

Circulation

Antiatherogenic effects of l-arginine in the hypercholesterolemic rabbit

J. Clin. Invest.

Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries

Circulation

High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells

Circulation

Tetrahydrobiopterin and endothelial nitric oxide synthase activity

Cardiovasc. Res.

Nitric oxide produced by endothelial cells increases production of eicosanoids through activation of prostaglandin H synthase

Circ. Res.

Review
The role of nitric oxide in cardiovascular diseases

Inhibition of proliferation, but not of Ca²⁺ mobilization, by cyclic AMP and GMP in rabbit aortic smooth-muscle cells