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446 Lipoproteins – Role in Health and Diseases

fibrous structures and separate cells.

perspective direction of research.

Endothelium vascular wall cells are involved into the interaction with the pathogenic LDL [5]. While macrophages are being overloaded with esterified cholesterol, oxysterols and other biologically active substances, including powerful enzymes with a wide spectrum of action, a foam cell is formed from the macrophage. Yet so far to its apoptosis the foam cell secrets a wide complex of interleukins, enzymes, mediators. Many of them induce a local inflammatory process, destruction of the surrounding intercellular substance, damage of the

Many factors are considered as the most important factors for atherosclerosis development risk. Among such factors an important role belongs to the so-called proatherogenic states, including chronic stress and metabolic syndrome (MS) [6]. The proatherogenic character of stress is connected, first of all, with the activation of free radical oxidation and hyperlipidemia development. One of the principal statements of all contemporary conceptions of the atherosclerosis pathogenesis is thought to be the destruction of the cell membrane structure,

It is well-known that free-radical processes play the leading role in atherosclerosis pathogenesis. So the antioxidants using in correction of proatherogenic states is fully explicable especially when we speak about natural antioxidants. Thus, the investigation of their biological effects under stress and metabolic syndrome is of grate interest and may be a

At the same time it is known that the enzymes associated with HDL, paraoxonase and PAFacetyl hydrolase can hydrolyse biologically active lipids of mm-LDL, destroy monocyte aggregates and decrease the endothelial activation of mm-LDL [8]. HDL also contain a high

Antioxidants protect LDL from peroxide oxidation and consequently from intensive uptake of LDL by macrophages decreasing the foam cell formation, the endothelium damage and possibility for lipids to infiltrate the intima. This condition supports the actuality of searching medicines for treating atherosclerosis, in which inhibition of the POL process plays an important part in the mechanism of their action [9]. Tocopherol, carotene, probucol,

The overwhelming majority of antioxidant substances used in pharmacotherapy are xenobiotics and so substrates of CYP system actvating ROS formation. Moreover some of

Therefore, the substances of natural, in particular, plant origins that possess a complex

Phenolic compounds are widely present in the world of plants; they are the most widespread product of the plant metabolism. Participation of polyphenols in redox processes to produce stable quinone structures by their phenolic forms reveals an antiradical direction of their action which provides their direct antioxidant activity. At present it has been proven that polyphenols as antiradical agents not only hinder the initiation of free radical oxidation, but also interrupt the chain of lipoperoxidation [10]. A great variety of

concentration of tocopherol due to which they can be free radical scavengers as well.

a number of plant medicines containing flavonoids are proposed as antioxidants.

them, such as probucol, leade to HDL-C decreasing.

activity draw attention of researchers.

which universal damage factor is peroxide oxidation of lipids (POL) [7].

Taking into account the leading role of the free-radical processes in atherosclerosis pathogenesis one can make a conclusion about expediency of using natural antioxidants in prophylaxis and correction of this disease. [15]. Consequently, the study of the antioxidant influence on the development of stress-reactions and metabolic syndrome (MS) with the purpose of prevention of harmful complications for the cardiovascular system is of undoubted interest.

A number of studies also confirm the ability of a natural antioxidant α-tocopherol to reduce the risk of cardiovascular system diseases developed in patients with MS. It has been found that administration of α-tocopherol limits oxidation and cytotoxicity of LDL in the blood plasma significantly, supports the vascular endothelial function and reduces the intensity of systemic inflammation in the conditions of MS. The inhibiting effect of this antioxidant on aggregation and adhesion of platelets, adhesion of monocytes to endothelial cells and the smooth muscle cell proliferation has also been shown. However, numbers of experimental studies confirm that the single use of α-tocopherol is not enough for prevention of cardiovascular diseases in patients with MS [16]. It has been determined that the use of αtocopherol in combination with ascorbic acid and aspirin (as a thrombolytic drug) is more effective [8]. In the ASAP study, the combination of vitamins E plus C was also tested, and this significantly decreased the intima-to-media progression rates in human. The ATBC clinical study used a combination of vitamin E and β-carotene in human as a secondary

prevention strategy; however, no benefit on major coronary events has been found. The large MRC/BHF Heart Protection Study (HPS) for secondary prevention also examined the benefit of the antioxidant combination (vitamins E and C and β-carotene).

A strong dose-dependent effect of α-tocopherol administration is one of the unwanted effects. It is known that even a slight increase of the α-tocopherol dose could affect lipoprotein oxidation, the endothelium function and the degree of systemic inflammation [12].

The results of Cambridge Heart Antioxidant Study (CHAOS) of using antioxidants in cardiology published in 1996 give the opportunity to say that in patients with true (confirmed by angiography) coronary atherosclerosis vitamin E administration (a daily dose of 544-1088 mg (400-800 МU) reduces the risk of non-fatal myocardial infarction. The overall mortality from cardiovascular diseases in this case does not decrease. A favourable effect is revealed only after one-year administration of tocopherol.

At the same time in the Heart Outcomes Prevention Evaluation (HOPE) study, which was devoted to the study of the action of both ramipril and vitamin E (400 МU/daily dose), it was found that use of this antioxidant during approximately 4.5 years did not cause any effect on either the primary (myocardial infarction, insult and death from cardiovascular diseases) or any other end points of research. In another large-scale study on the primary prophylaxis of atherosclerotic diseases in people at least with one risk factors (hypertension, hypercholesterolemia, obesity, preliminary MI of the closest relative or advanced age) vitamin E (300 МЕ/daily dose) was used during 3.6 years and did not reveal any effect on any of the end points (the incidence of cardiovascular events and death). The vitamin E effectiveness was also not confirmed for various other cases (hypercholesterolemia, the level of sportsmen training, sexual potency, retardation of aging processes, etc.).

Empirically vitamin E is used in various diseases; however, the majority of the reports about tocopherol effectiveness is based on the single clinical observation and experiment data. Nowadays there are no reliable results on the role of vitamin E in prevention of tumour diseases, though the ability to reduce formation of nitrosamines (potentially carcinogenic substances being formed in the stomach), to decrease the formation of free radicals and have antitoxic effects when using chemotherapeutic remedies is well-known. In addition, the long-term intake of vitamin E in the doses from 11 to 800 mg does not cause side effects.

In HDL Atherosclerosis Treatment Study (HATS) there was the treatment of atherosclerosis depending on the high density lipoprotein cholesterol (HDL-C) level; in 160 patients with coronary heart disease with the confirmed coronary artery stenosis and the low HDL-C level the higher (800 МU/day) dose of vitamin E than in HOPE was used. The treatment combination also included 1000 mg of vitamin C, 25 mg of β-carotene and 100 mg of selenium. The study lasted 3 years and revealed that antioxidants had no influence on the HDL-C level, but in combination with hypocholesterolemic drugs they reduced their effect on LDL-C and especially – on HDL-C.

The dominant carotenoid revealed in blood and various tissues (such as liver, kidneys, adrenal glands, ovaries and prostate) is lycopene. Due to its structure and mechanism of action lycopene belongs to the group of antioxidants; a lycopene molecule contains 13 double bonds, which can interact with free radicals. Like β-carotene lycopene can serve as a precursor of vitamin A. However, the lycopene antioxidant activity is two times stronger than that of vitamin A.

448 Lipoproteins – Role in Health and Diseases

prevention strategy; however, no benefit on major coronary events has been found. The large MRC/BHF Heart Protection Study (HPS) for secondary prevention also examined the

A strong dose-dependent effect of α-tocopherol administration is one of the unwanted effects. It is known that even a slight increase of the α-tocopherol dose could affect lipoprotein

The results of Cambridge Heart Antioxidant Study (CHAOS) of using antioxidants in cardiology published in 1996 give the opportunity to say that in patients with true (confirmed by angiography) coronary atherosclerosis vitamin E administration (a daily dose of 544-1088 mg (400-800 МU) reduces the risk of non-fatal myocardial infarction. The overall mortality from cardiovascular diseases in this case does not decrease. A favourable effect is

At the same time in the Heart Outcomes Prevention Evaluation (HOPE) study, which was devoted to the study of the action of both ramipril and vitamin E (400 МU/daily dose), it was found that use of this antioxidant during approximately 4.5 years did not cause any effect on either the primary (myocardial infarction, insult and death from cardiovascular diseases) or any other end points of research. In another large-scale study on the primary prophylaxis of atherosclerotic diseases in people at least with one risk factors (hypertension, hypercholesterolemia, obesity, preliminary MI of the closest relative or advanced age) vitamin E (300 МЕ/daily dose) was used during 3.6 years and did not reveal any effect on any of the end points (the incidence of cardiovascular events and death). The vitamin E effectiveness was also not confirmed for various other cases (hypercholesterolemia, the level

Empirically vitamin E is used in various diseases; however, the majority of the reports about tocopherol effectiveness is based on the single clinical observation and experiment data. Nowadays there are no reliable results on the role of vitamin E in prevention of tumour diseases, though the ability to reduce formation of nitrosamines (potentially carcinogenic substances being formed in the stomach), to decrease the formation of free radicals and have antitoxic effects when using chemotherapeutic remedies is well-known. In addition, the long-term intake of vitamin E in the doses from 11 to 800 mg does not cause side effects.

In HDL Atherosclerosis Treatment Study (HATS) there was the treatment of atherosclerosis depending on the high density lipoprotein cholesterol (HDL-C) level; in 160 patients with coronary heart disease with the confirmed coronary artery stenosis and the low HDL-C level the higher (800 МU/day) dose of vitamin E than in HOPE was used. The treatment combination also included 1000 mg of vitamin C, 25 mg of β-carotene and 100 mg of selenium. The study lasted 3 years and revealed that antioxidants had no influence on the HDL-C level, but in combination with hypocholesterolemic drugs they reduced their effect

The dominant carotenoid revealed in blood and various tissues (such as liver, kidneys, adrenal glands, ovaries and prostate) is lycopene. Due to its structure and mechanism of action lycopene belongs to the group of antioxidants; a lycopene molecule contains 13

benefit of the antioxidant combination (vitamins E and C and β-carotene).

of sportsmen training, sexual potency, retardation of aging processes, etc.).

revealed only after one-year administration of tocopherol.

on LDL-C and especially – on HDL-C.

oxidation, the endothelium function and the degree of systemic inflammation [12].

Lycopene is recommended as an adjuvant in the treatment of the following diseases: idiopatic male infertility, chronic prostatitis, preeclampsia and intrauterine growth retardation (IUGR), mastopathia, diabetes mellitus, cardiovascular diseases, leucoplakia, age-related degeneration of yellow spots and cataract [17]. As with other oxidants, lycopene is administered in immunodeficiency states against chronic infections and to reduce the harmful action of unfavourable environmental factors.

The most representative evidence of the antioxidants' positive role in cardiovascular diseases prophylaxis was obtained in the multicultural European community multicentre study on antioxidants, myocardial infarction, and breast cancer (EURAMIC), during which the relationship between the antioxidant status and acute myocardial infarction in patients from 10 European countries was determined. The protective action was proven only for lycopene. In the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) the high level of blood plasma lycopene is associated with decreased risk of acute coronary syndrome and insult. In Erasmus Rotterdam Health Study (ERGO, also called "Rotterdam Study") it has been proven that lycopene prevents development and progression of atherosclerosis.

The meta-analysis of 72 epidemiological studies conducted concerning the connection between the tomato intake and cancer has determined the associative feed-back between the blood plasma lycopene level and the risk of cancer in 57 studies and 35 from 57 obtained associations were statistically significant [18].

Probucol (phenbutol) is a hypolipidemic medicine and belongs to butyl phenol derivatives. Probucol is the medicine that is similar in structure to hydroxytoluene – the compound with the potent antioxidant properties.

The hypolipidemic effect of Probucol is caused by activation of non-receptor ways of LDL extraction from the blood. It is believed that the prominent antioxidant activity of probucol prevents LDL oxidation.

Probucol decreases the total cholesterol content in plasma due to intensification of the LDL catabolism at the final stage of cholesterol elimination from the organism. It also inhibits the cholesterol biosynthesis at early stages and to a small extent slows down the food cholesterol absorption. It does not influence the triacylglycerol and the VLDL content, but significantly decreases the antiatherogenic HDL level in the blood. It is believed that decrease of the HDL-C level reflects improvement of cholesterol esters transfer with HDL on acceptor lipoproteins due to increase of the cholesteryl ester transfer protein (CETP) activity.

In spite of undesired decrease in the HDL-C concentration probucol causes regression of xanthelasma; this effect is revealed best of all in patients with the most dramatic HDL-C decrease. This important observation demonstrates that the low HDL-C content is not undoubtedly a negative phenomenon. The data obtained in experiments with animals indicate that probucol due to its antioxidant properties prevents lipid peroxidation and thereby inhibits

the LDL uptake by macrophages, therefore, it inhibits atherogenesis. This allows suggesting that the therapeutic effect of the medicine may not be connected with its ability to decrease the LDL level. There is no clinical evidence of this hypothesis at the moment.

The medicine is absorbed slowly when taken internally, it is readily soluble in the adipose tissue releasing gradually into the bloodstream, and so its action is kept for a long time (up to 6 months after discontinuation of the treatment).

When using probucol in MultiVitamins and Probucol (MVP) research the renewal of the endothelium function in patients with IHD, decrease of restenosis cases after coronary angioplasty (when taking it at least 4 weeks before the procedure and further treatment during 6 months) was observed. Other antioxidants (α-tocopherol in high doses (700 mg per day), β-carotene and vitamin C) turned out to be ineffective.

Combined application of the endogenous antiradical antioxidants is of particular interest. In HPS (Heart Protection Study) along with the study of the simvastatin effectiveness the prophylactic action of antioxidants was investigated. The use of the vitamin complex (600 mg of vitamin E, 250 mg of vitamin C and 20 mg of β-carotene per day) lasted in average 5.5 years and did not reveal any differences in placebo groups and groups taking vitamins. Moreover, if the tendency exists, it reflects increasing of vascular events in the antioxidant intent-to-treat group. The action of antioxidants was compared with the effect of the combined use of simvastatin and nicotinic acid (niacin). Moreover, one of the groups received simvastatine+niacin and antioxidants. Angiographic and clinical data of this study were also disappointing with respect to the use of antioxidants.

Unfortunately, a great part of the compounds synthesized, which are used for pharmacocorrection of these states, are xenobiotics, so they can activate the free-radical formation process. Synthetic antioxidants, in particular probucol, can not be recommended for patient use because they decrease the HDL-C level.

The lack of antioxidant medicines popularity and the absence of traditions of their common use in practical medicine are caused a number of reasons: unsatisfactory previous study of this issue, complexity of adequate estimation of oxidation state parameters in the organism and the absence of the effective medicines with the antioxidant activity that are able to quickly reduce the consequences of the oxidative stress.

Therefore, the main indications for using antioxidants are excessively activated free-radical oxidation processes accompanying different pathologies. The choice of specific medicines, correct indications and contraindications for their use has not been developed yet and require further research.
