биохимия атеросклероза
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ing vitamin E [75]. It must be remembered that as the LDL is removed from its native environment and then oxidized, it is difficult to draw comparisons to an in vivo environment [76].
Direct Methods
A study of an animal model of atherosclerosis (apo-E knockout mice) demonstrated that autoantibodies against Ox-LDL recognize different epitopes of the complex structures that develop due to oxidative modification of the apolipoprotein moiety [77]. Holvoet et al. [78] developed a competition ELISA method to detect Ox-LDL in plasma using monoclonal antibody 4E6. This monoclonal antibody is directed against the apo B100 moiety of LDL that is generated when oxidative modification occurs due to the presence of midto long-chain aldehydes. Using this method, elevated levels of Ox-LDL have been shown to correlate well with CAD in heart transplant patients [78]. The limitation of this monoclonal antibody is that it binds to MDA-LDL as well as an array of other modified LDL particles [79].
Toshima et al. [80] also developed a simple sandwich enzyme immunoassay for human Ox-LDL. These authors used a monoclonal antibody FOH1a/DHL3 that reacts specifically against oxidized phophatidylcholine (oxPC) but not against native LDL, MDA-LDL, acetylated LDL, or glycated LDL. This monoclonal antibody was developed by using a homogenate of human atheromatous plaques from the aorta as the antigen. The authors were also able to show a relationship between circulating levels of Ox-LDL using this method and CHD, and showed that the relationship is superior to that of other markers of CHD, such as total cholesterol, triglycerides, or HDL levels [80].
Ehara et al. [79] developed a sandwich ELISA method to measure Ox-LDL levels using a mouse anti-Ox-LDL monoclonal antibody (DLH3) and an antiapolipoprotein B (apoB) polyclonal antibody. DLH3 is specific of Ox-LDL and does not bind to native or acetylated, glycated, or MDA-treated LDL. This method is highly sensitive to detecting minute amounts of Ox-LDL and avoids the interference of other plasma substances, although strictly speaking does not measure the plasma Ox-LDL levels as the LDL is separated from the blood before the testing. Using this ELISA method Ehara et al. [79] showed that Ox-LDL levels are related to the severity of the coronary syndrome, and thus could serve as a marker of cardiovascular events. It may be that the increased presence of circulating Ox-LDL acts as a destabilizing agent on plaque composition, most likely by enhancing the inflammatory processes and surface thrombosis [79].
The interest in the clinical role of Ox-LDL has been growing since the elucidation of its role in the progression of atherosclerosis. Unfortunately the ongoing study of the clinical role of Ox-LDL has been hampered by a lack in sensitive and specific markers of circulating Ox-LDL. It is currently apparent that this has been rectified with the development of direct ELISA
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methods for the testing of levels of circulating Ox-LDL and enable a direct comparison between different populations in order to speculate on the likelihood of that population developing atherosclerotic complications.
Use of Ox-LDL as a Marker of Vascular Disease
Studies have indicated an association between increases in the concentration of circulating Ox-LDL in patients and CAD [78]. Holvoet et al. [78] speculated that this increase could be due to a back diffusion of Ox-LDL from the atherosclerotic arterial wall and would be independent of plaque stability. Toshima et al. [80] studied the clinical relevance of circulating antibodies against OxLDL and found they were significantly higher in patients with CHD, than the control population. Based on their findings the authors [80] concluded that the Ox-LDL could be a possible risk marker for CHD. In a study by Ehara et al. [79] there was a significant positive correlation between the severity of acute coronary syndromes and the level of Ox-LDL, indicating that the levels of Ox-LDL relate to the instability of plaque in atherosclerotic lesions.
The idea that Ox-LDL and aOx-LDL could be used as a biomarker for CAD has been developed in populations that traditionally are vulnerable to increased CVD, such as type 1 and type 2 diabetes mellitus. Diabetes mellitus (DM) is associated with an increased risk of atherosclerosis; studies in these patients have shown evidence of the increased presence of Ox-LDL and aOxLDL [81, 82]. There is also evidence that there is increased concentration of Ox-LDL in hypertensive patients [26].
There are many diseases that have been studied and found to have evidence of increased Ox-LDL concentrations in populations at increased risk of developing heart disease. In prospective studies, antibodies to Ox-LDL have been shown to predict MI and progression of atherosclerosis in populations without autoimmune disease. As such these antibodies may be seen as markers of determinants of atherosclerosis such as lipid oxidation, a proinflammatory environment, endothelial dysfunction, and impaired vasodilation [25]. They may in fact be a useful marker for indicating individuals at increased risk of CVD [83, 84].
It appears that antibodies to LDL is a much more sensitive marker to atherosclerosis and CHD than the more traditional biomarkers used currently such as LDL concentration [84], sensitive enough that it may be useful in the identification of silent atherosclerosis in clinically healthy individuals [84].
OxLDL and Inflammation
It is clear that the evidence to support the oxidation hypothesis is compelling, it is also clear that there is also equally compelling evidence that oxidation is not a key process in the development of atherosclerosis. When results are
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equivocal it implies there is another causative factor not originally considered in the hypothesis. For the Ox-LDL hypothesis to remain viable, oxidation must be the initiating factor in atherosclerotic development, and at this stage, the evidence does not support this. There are avenues for foam cell development that do not rely on oxidation [3].
It is likely that this other factor is inflammation. It is clear that this inflammation is a key to atherosclerosis. Initially in the early 1980s, Ross [59] concluded that diets leading to the development of atherosclerosis produced inflammatory cellular adhesion to arteries. Since then many studies have established markers of inflammation, such as C-reactive protein a systemic marker of inflammation, as sensitive and specific markers of the development and progression of atherosclerosis. C-reactive protein may be a more sensitive marker of atherosclerotic development than traditional biomarkers such as cholesterol [85].
It is clear that there is an intertwined role of Ox-LDL and inflammation. The increased entry and decreased exit of inflammatory cells from the arterial intima would be expected to increase arterial inflammation. Similarly, Ox-LDL is able to upregulate a number of genes associated with inflammation such as MCP-1, and has been shown to alter the scavenger receptor (CD36) expression [3]. Due to the antioxidant clinical trials showing little or no efficacy in the protection or prevention of atherosclerosis, it must now be considered that oxidative events are the consequence of atherosclerosis.
It is likely that oxidation is not the causative agent in the development of atherosclerosis, but rather a by-product of inflammation. LDL oxidation, a key step for the development of atherosclerosis, therefore, could be a result of increased inflammation [3, 6].
Conclusion
Some indirect evidence has accumulated to support a link between Ox-LDL and the pathophysiology of atherosclerosis. To date intervention strategies for reduction of cardiovascular risk included increased intake of antioxidantrich foods and/or supplements for prevention of oxidation of LDL and the rate of atherogenesis. However, large clinical trials involving isolated antioxidants have failed to produce equivocal evidence to support involvement of Ox-LDL in the development of CAD. It is clear from these large trials that there is no evidence to support the use of supplements to treat or prevent CHD, in fact the only epidemiological evidence that has been sustained is that a high intake of fruits and vegetables is protective in CHD.
It is also important to distinguish whether inflammation increases oxidative stress, which further increases atherosclerosis or it is the increased oxidative stress that increases inflammation to accelerate atherosclerosis. This answer is likely to lie in the former. If that is the case, and taking into consideration the role of redox processes in many cell signaling and other normal cellular
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activities the ubiquitous prophylactic supplementation with antioxidants may in fact be damaging.
Recent studies have implicated a role for inflammation in the development of atherosclerosis, among other chronic lifestyle diseases. It is well recognized that oxidative stress has a role in, and is a product of, the inflammatory process. The evidence does not appear to support the primary role of oxidative stress in atherogenesis, however the evidence is more favorable for inflammation as the initiating factor in the development of atherosclerosis and through this the development and progression of CHD. Therefore, there is a need to separate oxidative stress and inflammation and their individual and synergistic effect on CHD to improve strategies for the prevention of this number one killer.
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Biochemistry of Atherosclerosis edited by S.K. Cheema, Springer, New York, 2006
25
Dietary Fatty Acids and Stroke
GENE R. HERZBERG
Abstract
The relationship of dietary fatty acid intake and the risk of stroke has been the subject of numerous investigations. The results of studies of the effects of saturated fat have been conflicting making it difficult to reach a conclusion about saturated fat and stroke. Intake of n6 fatty acids, particularly linoleic acid, appears to be inversely related to stroke risk. Although concerns have been expressed about a possible increase in risk of hemorrhagic stroke related to long chain n3 intake caused by changes in the clotting ability of blood, the results suggest that these fatty acids, when consumed at levels found in typical Western diets, reduce the risk of ischemic stroke with no increase in risk of hemorrhagic stroke.
Keywords: blood clotting; diet; fatty acids; hemorrhagic stroke; ischemic stroke; n3 fatty acids, n6 fatty acids; saturated fatty acids
Abbreviations: EPA, eicosapentaenoic acid 20:5 n3; COX-2, cyclooxygenase; TX, thromboxane; PUFA, polyunsaturated fatty acids; DHA, docosahexaenoic acid 22:6 n3; P/S, polyunsaturated/saturated ratio; ALA, alpha-linolenic acid, 18:3 n3
Introduction
Stroke is a leading cause of cardiovascular deaths. Annual stroke incidence in Europe, Russia, Australasia, and the United States for those 45–84 years of age is between 0.3% and 0.5% [1]. Worldwide, stroke is the second leading cause of death accounting for 4.4 million deaths in 1990 [2] and results in significant morbidity. The death rate due to stroke varies among countries but is between 17% and 38% [3]. Of those who survive, approximately one half will remain permanently disabled and one half will be capable of independent living [4].
Stroke results from an interruption in the blood supply to a portion of the brain. The extent of the injury depends on the location and severity of the stroke. Strokes can be broadly divided into two categories namely, hemorrhagic and ischemic. Hemorrhagic strokes are a result of the rupture of a blood vessel with the resulting loss of blood supply. Ischemic strokes are the
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