© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Oxidative stress, F2-isoprostanes and endothelial dysfunction in hypercholesterolemia
aCNR Institute of Clinical Physiology, University of Pisa, Via Roma 67, 56126 Pisa, Italy
bDepartment of Internal Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy
cDepartment of Oncology, Division of Pharmacology, University of Pisa, Via Roma 67, 56126 Pisa, Italy
* Corresponding author. Tel.: +39-50-583-288; fax: +39-50-553-461 palombo{at}po.ifc.pi.cnr.it
See article by Wilson et al. [9] (pages 601–607) in this issue.
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1 Introduction |
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 Top 1 Introduction 2 Hypercholesterolemia and...3 Endothelial dysfunction and...4 The double facet...5 ConclusionsReferences |
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Hypercholesterolemia is reported to be associated both with enhanced oxidative stress, related to increased lipid peroxidation [1], and with augmented susceptibility to coronary vasoconstriction [2]. The abnormal coronary vasoreactivity is mainly attributed to endothelial dysfunction, which in hypercholesterolemic man has been demonstrated by several approaches, including coronary and forearm blood flow response to acetylcholine (ACh) [3,4], and flow-mediated dilation [5]. An increased generation of oxidized LDL is a major factor responsible for the vascular damage related to high cholesterol levels, and oxidative stress leads to increased breakdown and/or reduced bioavailability of NO in a number of experimental and clinical models [6]. F2-Isoprostanes, namely 8-epi-prostaglandin F2
(8-epi-PGF2), have been recently proposed as reliable markers of oxidative stress in vivo [7,8].
Wilson et al. [9] in their study demonstrate that 8-epi-PGF2 causes a dose-dependent vasoconstriction in vitro, in pig coronary strips obtained from normal and hypercholesterolemic animals. Coronary vasoconstriction induced by 8-epi-PGF2 is shown to be modulated by endothelial NO, being increased after both endothelial denudation and L-NMMA administration in control animals. Hypercholesterolemic vessels (HV), in turn, show an increased coronary vasoconstriction to 8-epi-PGF2 which is comparable to that observed in normal animals following endothelium denudation, specific for 8-epi-PGF2, not being found with other vasoconstrictor prostanoids, and is attenuated by pretreatment with L-arginine or the NO donor NOR-3. These observations suggest a tonic vasoconstrictor activity dynamically opposed by NO, with the net vasomotor effect resulting from the balance of the two systems.
Furthermore, 8-epi-PGF2 in hypercholesterolemic animals shows increased circulating levels and increased deposit on the intimal surface of the vessel. The association between increased circulating level and increased intimal deposition of 8-epi-PGF2 supports the pathogenetic role of F2-isoprostanes in determining vascular damage, and puts forward the hypothesis of the intimal disease as a dynamic process involving the arterial wall in the early stages of atherosclerosis, where the morphologic abnormality may be related to possibly reversible biochemical and histochemical changes more than to permanent structural abnormalities. Such an observation might help to explain significant changes detectable in large artery geometry in hypercholesterolemic man with endothelial activation after relatively short-term cholesterol lowering therapy [10].
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2 Hypercholesterolemia and oxidative stress |
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Top1 Introduction2 Hypercholesterolemia and...3 Endothelial dysfunction and...4 The double facet...5 ConclusionsReferences |
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Hypercholesterolemia is associated with an impaired endothelium-dependent relaxation, i.e. a diminished bioactivity of NO. Altered vasomotion in hypercholesterolemia is dependent on increased levels of oxidized LDL, which in ex vivo studies are shown to be able to impair signal transduction between endothelial cell surface receptors and NO production [11], to inhibit NO synthase activity [12], and to inactivate NO released from endothelial cells [13]. This last mechanism would lead to an accelerated breakdown of readily formed NO by augmented superoxide activity, being responsible for a decreased NO bioavailability [2,14]. The observation that low density lipoproteins (LDL) increase superoxide release in cultured endothelial cells in a fashion which seems to be dependent on eNOS activity [6] may explain the apparent paradox of NO synthase activation, increased NO generation and endothelial dysfunction in hypercholesterolemia. An indirect evidence that oxidative stress plays a major role in determining endothelial dysfunction also in human hypercholesterolemia comes from the observation that treatment with intraarterial infusion of vitamin C improves endothelium-dependent vasodilation in the forearm of hypercholesterolemic subjects [15].
Previously reported evidence suggested an accelerated degradation of endothelium-derived NO by superoxide anions (O2–) in hypercholesterolemic vessels (HV): in a study from Ohara et al. [14], vessels from cholesterol-fed rabbits produced threefold more O2– than those from normocholesterolemic rabbits (NV). Quite interestingly, endothelial removal decreased O2– production in HV, indicating that the majority of superoxide in early atherosclerosis is produced in the endothelium. The xanthine oxidase inhibitor oxypurinol normalized O2– production in HV and improved ACh-induced relaxation in HV, while having no effect in NV. Thus, the study of Ohara et al. [16] provided evidence that the endothelium itself can be a source of superoxide anions in hypercholesterolemic vessels, which ultimately may result in inactivation of endothelium-derived NO to the one-electron oxidation product NO2–, consequently reduced NO bioavailability, and in an impaired endothelium-dependent relaxation [16].
The hypothesis that NO release from hypercholesterolemic arteries (rabbit aorta) could be enhanced rather than impaired was raised from Minor et al. in 1990 [17], suggesting that other mechanisms than a deficiency of the enzyme responsible for NO synthesis may underlie endothelial dysfunction in hypercholesterolemia.
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3 Endothelial dysfunction and coronary tone |
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Top1 Introduction2 Hypercholesterolemia and...3 Endothelial dysfunction and...4 The double facet...5 ConclusionsReferences |
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Endothelium-derived NO contributes to resting epicardial and microvascular coronary tone, and coronary risk factors including hypercholesterolemia are associated with reduced resting and stimulated bioavailability of NO from the human coronary circulation [18]. A defective endothelium-mediated vasodilation is a mechanism underlying an inappropriate vasoconstrictor response to stimuli inducing coronary vasodilation in presence of normal endothelium. In patients with hypercholesterolemia and coronary artery disease, coronary dilator response to ACh is inversely related to LDL susceptibility to oxidation and improves more when the antioxidant agent probucol is added to cholesterol-lowering treatment as compared to conventional therapy alone, thus suggesting a major role for oxidized LDL in the impairment of the endothelium-dependent coronary vasodilation [9–21].
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4 The double facet of F2-isoprostanes: markers of oxidative stress and modulators of coronary tone |
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Top1 Introduction2 Hypercholesterolemia and...3 Endothelial dysfunction and...4 The double facet...5 ConclusionsReferences |
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The F2-isoprostanes, a family of novel prostaglandin isomers generated by free radical-mediated peroxidation of arachidonic acid and LDL independently from cyclooxygenase [7], are generated in situ and subsequently recovered in blood and urine [22]. Proposed as potential markers of in vivo oxidative stress in atherothrombotic disease [8], their circulating levels have been reported to be increased in hypercholesterolemic patients [23], and increased accumulation has been recently documented in coronary arteries from patients with coronary artery disease as compared to dilated cardiomyopathies and controls [24]. Furthermore, urinary excretion of 8-epi-PGF2
has been reported to be increased in patients with familial heterozygous hypercholesterolemia and to be lowered by dietary and/or drug cholesterol lowering treatment [25]. Their vasoconstrictor activity on several vascular beds, such as aortic and coronary, in vitro was recently reported [26], but their possible role in control of arterial tone, namely the coronary one, in physiologic and disease states was not yet demonstrated before the contribution of Wilson et al. [9]. |
5 Conclusions |
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Top1 Introduction2 Hypercholesterolemia and...3 Endothelial dysfunction and...4 The double facet...5 ConclusionsReferences |
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A major contribution of the work of Wilson et al. [9], capable of representing a reference position in understanding the relations between hypercholesterolemia, endothelium-mediated coronary tone and oxidative stress, stands on the clear demonstration that a decreased NO bioavailability secondary to enhanced oxidative stress resulting from lipid peroxidation is responsible for the increased coronary vasoconstriction in hypercholesterolemia. Actually, the paper provides further support to the hypothesis that, despite in very advanced atherosclerosis the expression of NO synthase in endothelium clearly declines, in several disease conditions including hypercholesterolemia and earlier stages of atherosclerosis, NO production is not altered but its bioavailability is reduced because of oxidative inactivation by excessive production of the superoxide anion O2– [27]. The observation of an increased dose-dependent vasoconstriction to 8-epi-PGF2
in coronary arteries with intact endothelium from hypercholesterolemic pigs nicely mirrors the finding of increased time-dependent O2– generation observed by Ohara et al. [14] in rabbit aorta with endothelium from hypercholesterolemic rabbits.
Several cellular sources of reactive oxygen species are known, including also endothelial NO synthase, cyclooxygenase, lipoxygenase. Also this observation has relevant implication for the clinicians, focusing on the reduction of oxidative stress through plasma cholesterol lowering as primary therapeutic goal, as well as on the administration of NO donors or precursors as additional measure for restoring a physiologic balance between coronary vasoconstrictor and vasodilator activity: oxidative stress from one side increases breakdown and decreases bioavailability of NO, whose tonic release is responsible for keeping the vasculature in an adequately dilated state, and from the other increases generation of vasoconstrictor products, namely prostanoids. Finally, 8-epi-PGF2 reveals its double facet of marker of oxidative stress associated to lipid peroxidation and trigger of vasoconstriction in presence of wounded endothelium.
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Acknowledgements |
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Authors are indebted to Dr Corrado Blandizzi MD, and to Professor Mario Del Tacca MD, from the Department of Oncology, Division of Pharmacology, of the Pisa University, for their cooperation. Elena Barberini is also acknowledged for editorial assistance.
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