Endothelial dysfunction and intimal-media thickness are considered the early steps in atherosclerosis. Rassel Ross8 has modified atherosclerosis patho-genetical theories because numerous pathophysiological observations in humans and animals have led to the formulation of the response-to-injury hypothesis of atherosclerosis. Each characteristic lesion of atherosclerosis represents a different stage in a chronic inflammatory process in the artery. The lesions of atherosclerosis represent a series of highly specific cellular and molecular responses that can be described as an inflammatory disease. Possible causes of endothelial dysfunction leading to atherosclerosis include hypercholesterol-aemia, hypertension, diabetes mellitus, cigarette smoking, elevated plasma homocysteine concentrations, infectious microrganisms and ageing. Framingham's studies have shown how each factor and combination of these factors are associated with atherosclerotic diseases.9 All these factors can be associated with oxidative stress.10-15 The beneficial effect of alpha-tocopherol and ascorbic acid is mediated by their antioxidant actions in preventing atherosclerosis. On the other hand, the effect of alpha-tocopherol could also be mediated by its antiplatelet and anti-coagulant actions, which would prevent the thrombotic consequences of atherosclerosis.16'17
Cigarette smoking, hypertension, diabetes mellitus, genetic alterations, elevated plasma homocysteine concentrations, infectious microorganisms, such as herpes viruses or Chlamidia pneumoniae, have proinflammatory actions, increasing the formation of hydrogen peroxide and free radicals such as superoxide anion and hydroxyl radicals in plasma. These substances reduce the formation of nitric oxide (NO) by endothelium. Nitric oxide is a free radical with an unpaired electron in its highest orbital. This is why it behaves as a potential antioxidant agent by virtue of its ability to reduce other molecules. In vitro experiments support this concept inasmuch as NO is able to inhibit lipid peroxidation. However, NO is rapidly inactivated by the peroxide anion (O2_) to form peroxynitrite (NO3~) which is a potent oxidant. Therefore, in the presence of O2~, NO behaves as a potent pro-oxidant. This is the mechanism that accounts for the low-density lipoprotein (LDL) oxidation that occurs when NO and O2~ are simultaneously present in the medium. As NO and O2~ are simultaneously released by cells, such as endothelial cells, the balance between these two radicals is crucial in understanding the net effect of NO on lipid peroxidation. Thus an excess of NO will favour lipid peroxidation inhibition, while an excess of O2~ or equimolar concentrations of NO and O2~ will induce lipid peroxidation. Modulation of this balance may have important clinical implications, particularly in the atherosclerotic process, in which oxidative stress seems to play a pivotal role in the onset and progression of vascular lesions.
Several studies have strongly suggested that enhanced oxidative stress may represent an important trigger for atherogenesis elicited by angiotensin II (Ag II). Free radical formation mediates some of the effects of hypertension. Angiotensin II concentrations are often elevated in patients with hypertension and it is a potent vasoconstrictor. It also increases smooth-muscle hypertrophy and lipoxygenase activity, which, in turn, can increase inflammation and the oxidation of LDL.
Grienling et al.18 examined the effect of Ag II on superoxide anion (O2_) production by smooth muscle cells and demonstrated that 4 to 6 hour exposure of these cells to Ag II elicited enhanced production of O2~. This effect was mediated by NADH and NADPH oxidase activation probably via intracellular mobilization of fatty acids such as arachidonic acid. Experimental studies in animals demonstrated that Ag II infusion enhanced simultaneously blood pressure and vascular production of O2~; this last effect was dependent upon NADH/NADPH oxidase, further suggesting the role of this pathway in Ag II-mediated O2~ production. These findings have important pathophysiological implications owing to the effect of O2~ on vascular motility. The oxidative stress may have a role in hypertensive patients, in whom a reduced vasodilating response to acetylcholine has been demonstrated. Thus, in patients with hypertension, the administration of the antioxidant vitamin C has been able to restore acetylcholine-induced vasorelaxation, suggesting a role for oxygen free radicals in inducing vascular dysfunction in patients with hypertension. Cigarette smoke contains large amounts of free radicals which may degrade nitric oxide release from the endothelium and also produce highly reactive intermediates resulting in endothelial injury. Antioxidants such as vitamin E can also reduce free-radical formation by modified LDL.19
Blood analysis of lipid peroxides or measurement of urinary excretion of isoprostanes has provided evidence that oxidative stress is enhanced in patients with diabetes.20 The impact of these data in the context of atherosclerosis progression is still unclear, but there is some evidence supporting a role for oxidative stress in contributing to deteriorating vascular disease. For instance, an important finding is the demonstration that endothelium-dependent vasodilation is reduced in patients with diabetes and that vitamin C is able to prevent it, so indicating a role for oxygen free radicals in reducing vasodilatory property of endothelium.21 Oxidative stress could also contribute to worse metabolic disturbance by interfering with glycaemic control. Thus it has been demonstrated that, in diabetes, oxidative stress impairs insulin activity and antioxidants prevent it.22 That hyperglycaemia is a risk for enhanced oxidative stress has been further corroborated by a study in patients with type II diabetes, in whom an increased urinary excretion of PGF2m-III, which derives from arachidonic acid and interaction with oxygen free radicals, has been demonstrated.23 It is of note that a significant reduction of urinary PGF2cx-III was observed when patients underwent a strict glycaemic control, further reinforcing the relationship between hyperglycaemia and oxidative stress.
Hyperglycaemia may enhance oxidative stress and in turn induce vascular damage via several pathways, including the formation of the advanced glycated end products that are proatherogenic and prothrombotic (Fig. 5.1 panel C).24 Furthermore, glucose may alter the balance between free radicals such as O2* and NO in endothelial cells; thus NO exerts its vasodilatory and antioxidant effect unless it is converted to ONOO by interaction with O*. This deleterious effect occurs in endothelial cells exposed to glucose, which, in fact, favours the formation of O2* and in turn promotes oxidation.25
An interesting mechanism potentially accounting for enhanced production of reactive oxygen species (ROS) by glucose is reported in Fig. 5.1. Hyper-glycaemia was shown to enhance endothelial O2* generation via activation of cyclooxygenase pathway which is known to generate ROS with a mechanism
involving NAD(P)H oxidase.26 The potential role of this enzyme in inducing oxidative stress has been recently demonstrated by Guzik et al. who studied the expression of NAD(P)H oxidase in the vessel wall of people with and without diabetes.27 They found that, compared with controls, vascular expression of NAD(P)H oxidase submits, p22 phox and p47 phox, were overexpressed in those with diabetes.
There is experimental and clinical evidence indicating that hypercholesterolemia is associated with enhanced oxidative stress. Oxygen free radicals, such as O2*, and F2-isoprostanes, have been found elevated in the artery of hypercholesterolaemic animals and in the urine of patients with high serum cholesterol respectively.28'29 The relevance of these findings in the context of the pathophysiology of atherosclerosis is unclear, even if there is some evidence that in this setting oxidative stress may have a role in reducing the vasodilation of endothelium.30 Conversely, these is no evidence yet that the increase of these markers actually represents a marker of progression of atherosclerotic disease.
Two hypotheses can be suggested to explain why hypercholesterolaemia enhances oxidative stress (Fig. 5.1, panel A,B). Cholesterol has been recently shown to activate the metabolism of the arachidonic acid pathway,31 which in turn seems to be associated with NAD(P)H oxidase activation.26 This hypothesis has been recently underscored by our group showing that platelet incubation with cholesterol enhanced O2* production and that inhibition of PLA2 orNADPH oxidase enzymes significantly reduced O2 formation (Fig. 5.1 panel B).31
The cascade of cholesterol biosynthesis may represent another pathway leading to enhanced oxidative stress. Intracellular metabolism of mevalonate leads, in fact, to the formation of protein isoprenylation, which has a key role in the production of proinflammatory and pro-oxidant cytokines such as tumor necrosis factor alpha (TNF; Fig. 5.1, panel A).32 Accordingly, treatment of hypercholesterolaemic patients with an inhibitor of HMG-CoA-reductase was associated with reduced monocytes formation of TNF, suggesting a relationship between cholesterol and intracellular formation of pro-oxidant cytokines.33 The association between hypercholesterolaemia and oxidative stress has been further corroborated by an interventional study with statin in people with hypercholesterolaemia in whom simvastatin reduced the urinary excretion of PGF2cx-III, probably by lowering serum cholesterol.34 However, the existence of a mechanism independent of cholesterol lowering was not investigated. The relationship between hypertriglyceridaemia and oxidative stress has not been fully investigated. We found only one report aimed at analysing whether people with hypertriglyceridaemia had enhanced oxidative stress. Pronai et al. measured scavenging property and O2* formation by peripheral monocytes of hypertriglyceridaemic patients with and without diabetes.35 They found a significant positive correlation between O2* generation and plasma triglycerides and a significant negative correlation between superoxide scavenging property and plasma triglycerides.35
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