ReviewAntioxidants and endothelium protection
Introduction
Considered for a long time as merely a semi-permeable membrane, the endothelium in the last 20 years has gained the full title of a complex organ system that controls vascular homeostasis by integrating signals between the vascular wall and the vessel lumen. Today, it is widely accepted that the endothelium plays important roles in maintaining a normal vascular tone and blood fluidity, reducing platelet activity and leukocyte adhesion, and limiting vascular inflammatory reactions [1]. Under normal conditions, it regulates vascular homeostasis by elaborating a variety of factors that act locally in the blood vessel wall and lumen, such as nitric oxide (NO), prostacyclin and endothelin. However, in particular situations the endothelium can also modify its phenotype facilitating vasoconstriction, inflammation, and thrombotic events. These abnormal responses manifest with conditions, such as hypercholesterolemia, hypertension, diabetes mellitus, and occur in the absence of any morphological change of the vessel [2]. Interestingly, consistent evidence suggests that they are precursors of atherosclerosis and predictors of future vascular events [3]. The etiology of these altered endothelial functions is multi-factorial, and the mechanisms underlying them are complex and not yet fully elucidated. Among these factors, altered receptor signaling due to membrane changes, alterations of endothelium nitric oxide synthase (eNOS) expression and activity, decreased availability of tetrahydrobiopterin, and increased generation of superoxide radicals, all have been considered responsible for these alterations [4]. However, the most proposed mechanism implicated in the pathogenesis of endothelial dysfunctions is related to an increased production of reactive oxygen species (ROS). This would deplete the bioavailable NO and exacerbate local oxidative stress by directly reacting with NO to form peroxynitrite, which in turn, would further sustain an oxidative injury to the endothelium [5]. If the hypothesis that an imbalance between ROS formation and the capacity of the endothelium to destroy them plays a causative role in these altered endothelial functions, one could anticipate that molecules with the capacity of scavenging ROS, namely antioxidants, would reverse or prevent them. Thus, any pharmacological intervention with exogenous antioxidants should protect vascular endothelium specifically via a ROS-scavenging activity and the restoration of NO bioavailability.
In this review, I will focus my attention on the role that exogenous antioxidants play in protecting normal endothelial functions.
Section snippets
Antioxidants and endothelial dysfunction
The term endothelial dysfunction (ED) has been used very broadly in reference to several pathological conditions, such as altered anti-coagulant properties of the endothelium or dysregulation of vascular remodeling. However, most recently the term ED commonly refers to a reduced endothelium-dependent vasodilator capacity of the coronary and peripheral circulation to acetylcholine. Since, it is known that this type of vasorelaxation is related to the production of NO from endothelial cells,
Antioxidants and leukocyte–endothelium interactions
In addition to the changes in endothelium-dependent vasodilation, ROS have also been studied in relation to leukocyte–endothelial interactions. It is known that these circulating cells can be source of ROS, and their activation and migration from the circulation to area of vascular damage may play a significant role in the pathogenesis of altered endothelial function [43], [44], [45]. Leukocyte adhesion and penetration of the endothelium can be initiated by a number of inflammatory cytokines,
Antioxidants and endothelial cell thrombotic and fibrinolytic properties
Endothelial cells are the source of a number of components implicated in both thrombosis and fibrinolysis, which confer another extremely important property to the endothelium: the maintenance of a delicate balance between pro and anti-thrombotic events. In a physiological situation, endothelial cells possess an excess of plasminogen activators, thrombomodulin, and prostacyclin, all of which protect against pro-coagulant, pro-thrombotic and anti-fibrinolytic states. However, the endothelium can
Antioxidants and endothelial cell apoptosis
Several experimental approaches using different types of endothelial cells have clearly shown that endothelium can undergo apoptotic reactions under oxidative stress and in the presence of oxidized lipids, and that Vitamins C and E can prevent these events [92], [93]. Thus, oxidized LDL or their constituents oxysterols have been reported to induce apoptosis in endothelial cells as well as in smooth muscle cells [94]. This phenomenon is associated with an increase in caspase-3 activity and the
Non-antioxidant mechanisms of putative antioxidants and endothelium protection
In recent years, a growing body of evidence has been accumulating in support of the concept that the role of some antioxidants goes beyond their antioxidant actions. This novel idea has been particularly true for Vitamin E, for which in the last 10 years several non-antioxidant effects, most of which relevant to endothelium homeostasis, has been described. They include effects on cell enzymatic pathways, cell signaling, and regulation of gene expression.
The first report showing that Vitamin E
The antioxidant paradox
As mentioned earlier, many of the altered endothelial functions described in this paper are considered precursors of vascular atherosclerosis, and antioxidants have a beneficial effect on them. This observation would support the hypothesis that these compounds should also affect atherogenesis. While the vast majority of animal studies showed that administration of antioxidants has in fact ameliorated disease process in experimental models of atherogenesis, the outcomes of clinical trials have
Conclusion
Antioxidants can regulate and protect several aspects of endothelium functions mainly through antioxidant mechanisms, however they can also display properties that are related to different activities. Thus, antioxidant therapy and in general agents designed to scavenge ROS, whilst potentially acting through a pure antioxidant mechanism, may also be operating through mechanisms unrelated to an antioxidant activity. From the data in the literature, and in particular from the in vivo studies it is
Acknowledgement
Work in the author's laboratory was funded by the National Institute of Health and the American Heart Association.
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