ReviewThe role of nitric oxide in cardiovascular diseases
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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