Biological activity of high-density lipoprotein. Rapovets V.A. Cardiologist of the Policlinic. Belarus. From Lechebnoe delo.N6.2017. p.43-45. ISSN2219-6404 Summary. ISCHEMIC heart disease remains the leading cause of death and disability in Europe and the United States. Despite significant progress in the correction of atherogenic lipoproteins, remains unresolved question of pharmacological effects on high density lipoprotein cholesterol (HDL- C). Recent studies have revealed heterogeneity of structure, metabolism, biological activity of HDL particles. In the face of large HDL transformation revealed atherogenesis, which leads to a deterioration in their evaluation function. Keywords: cholesterol, high density lipoprotein, atherosclerosis. CVD remains the leading cause of death and disability in Europe and the United States. Despite significant progress in the correction of atherogenic lipoproteins, it remains unresolved the question of the pharmacological effects on cholesterol levels of high density lipoprotein (HDL). Recent studies have revealed heterogeneity of structure, metabolism, biological activity of HDL particles. In atherogenesis conditions revealed a significant transformation of HDL, leading to a decrease in their sacrificial function. Keywords: cholesterol, high density lipoprotein, atherosclerosis. Rapovets V. Traditionally it is believed that the higher the content of cholesterol of plasma, the more evident the protective function of HDL. And for the prevention of cardiovascular disease (CVD) is to increase this figure. So about data Frjemingem research, low levels of CHOLESTEROL HDL are reliably more powerful lipidic risk factor than high levels. In at least five different population studies have confirmed the close correlation between ISCHEMIC heart disease and low levels of HDL CHOLESTEROL, not dependent on other factors. Among white Americans average HDL level is 1.2 mmol/l (45 mg/dl) for men and 1.4 mmol/l (55 mg/dl) in women [2]. Consistent with the data on the varying risk ISCHEMIC heart disease representatives of both sexes, it is shown that the levels of HDL-C in women on average 25% higher than that of men. A tendency to raise their levels under the influence of estrogen and decrease under the influence of androgens. Low levels of CHOLESTEROL HDL in women with diabetes and obesity, that significantly increases the risk of ISCHEMIC heart disease Centenarians have levels LP this class is usually high, that may be partly a family character. In recommendations [3] cardiovask risk screening level of HDL-C is recognized as a strong risk factor (class I, level c). Prior to the treatment of Dyslipidemia recommended analysis of HDL-C (class I, level c) does not require treatment to control LHD-C (class 3 level). Daily intake of alcohol in small quantities is combined with a reduced risk of developing ISCHEMIC heart disease and high levels of HDL The mechanisms are unknown. In patients with metabolic syndrome, by slowly increasing slimming plasma LHD-C. And fast slimming, over 4 kg per month, this figure falls ( Wirth A., 2006). When conducting preventive activities was foundthat tobacco use is accompanied by decreasing levels of HDL-C , and regular physical activity- their increase. Regular physical workout leads to growth levels HDL-C persons after myocardial infarction. It has been proven that a diet low in fat and a high percentage of carbohydrates leads to lower levels of LDL-C, HDL-C, and TG. A decrease in body weight and increase physical activity increases the concentrations of LHD-C [9]. In study Kaiser Permanente it is established, that each increase in level of ch HDL at 5 mg/dl associated with a 4% reduction in the risk of hospitalization due to heart disease or stroke a downgrading of HDL-C to 6.5 mg/dl in turn increase dIvalo riskand hospitalization at 11%. According to a study NATS from 160 patients with ischemic heart disease was confirmed angiographic stenosis of the coronary arteries and the low level of HDL-C. appointment of vitamin e a day, 800 mg, vitamin c 25 mg, 100 mg, betacaroten Selena, simvastatin, niacin conducted 3 years. In the Group of simvastatin + niacin set HDL-C by 26%, the low incidence of cardiovascular events (SSA)-3%. In the Group of antioxidants-21% of CVD, under simvastatin + niacin + antioxidants-14% . appointment of magnesium 20 mmol (487mg) a day for 8 weeks reliably reduced the level of cholesterol in the blood plasma to 1.3 mmol/l (Parki P. S ., 1990). In study ALPINE appointment of sick AG atenolol and reduced HDL CHOLESTEROL level hypotiazid and increased LDL cholesterol levels [10]. FISH -17 showed that hypertension patients on monotherapy metoprolol resulted in a significant increase in TG and HDL. SLIP treatment of sick AG Verapamil 240 mg per day reliably increased HDL levels. In triale TOMHS when treating sick AG HDL levels declined by 0.6 + _0, 7 mg \ DL in Group acebutolol 400 mg per day and increased by + 0.2-0.7 mg \ DL in Group of amlodipine 5 mg per day as well as at 0.6 +-0.8 mg \ DL in Group hlortalidon 15 mg per day. In study using MRI it was found that u drives her LCAT gene mutations with reduced level of XC HDL often diagnosed atherosclerosis of the carotid arteries (Duivenvoorden et al, 2011 ). Low levels of HDL CHOLESTEROL was associated with a poor survival rate after surgery aorto-coronary bypass surgery [2]. HDL represent a complex group of particles moving about 20% of the total plasma cholesterol [1 ] . Figure. 1. HDL Subclasses and their functions. Plasma is dominated by spherical HDL [6 ] They are large sizes, from 8 to 12 nm in the gidrofob nucleus contain esters of CHOLESTEROL and triglycerides (TG) particle density. two main subclasses of HDL. HDL 2 is a large, light, rich lipids. HDL3-smaller particles dense, rich in protein. Gel electrophoresis method separated subfraction of HDL, in descending order of the size of this HDL2b, 2a, 3a, 3b,3c. Established the predominance of free cholesterol on ethers XR sfingomielina on fosfatidilholin for HDL2v with a decrease in proportion to the right to 3s. Disko group HDL are small size, less than 7 nm. Contain less lipid, less than 30%, and more apolipoproteid A1 (apoA1). recent predominate among proteins HDL (70%). Moving amfipatic α -Helix apoA1 actively bind the lipids and perform the basic function of HDL. Using two-dimensional electrophoresis, open subspecies HDL is pre β -particles containing apoA1 and phospholipids. HDL carry out reverse transport of CHOLESTEROL from the peripheral tissues, including the walls of the arteries to the liver. poor and rich in lipids apoA1, small particles of HDL cause reducing atherosclerotic plaque, exercising the outflow of HS from macrophages by CTP1 (cassette transport protein). This is due to the greater turnover of superficial layer of PL and apoA1 conformation. Large HDL because their more number through ABCG1 transported HS and 7-ketosteriny. And by the Decepticon-class receptors in type 1 (SR-B1) absorb esters cholesterol. Without receptors passes passive diffusion cholesterol on the concentration gradient. Small dense LDL protects HDL3 from peroxide oxidation of free radicals. Aldehydes and oxidized FL restored by oxidation of metioninovyh residues apoA1. Spherical HDL more than disko group, inhibit the synthesis of proinflammatory cytokines, adhesion of monocytes to adhere to, the expression of adhesion molecules on endothelial cells, activation of neutrophils and their infiltration in the walls of arteries. HDL3 inhibit apoptosis in endothelial cells extinguish and caused by growth factors in migration and survival. stimulate endothelial cells. Reduce output in the cytoplasm of cytochrome c and factor in the induction of apoptosis, HDL2 through HDL3. SR - (B) 1 and sphingosine-1-phosphate trigger phosphorylation of endothelial NO -synthase. Stimulate synthesis of prostacyclin (PGI) 2. such a mechanism inherent to Nicotinic Acid and dalcetrapib. HDL2, having apoE, inhibit Platelet Activation, tissue coagulation factor x, (V) and, (VIII) and factor. During an infection, HDL through apoA1 link and utilize the circulating Lipo-polysaccharides. Dense HDL 15-21 nm in diameter, through the APO (L) 1, apoA2, apoS1, apoS2, apoS3 Lysis trypanosomes. Atherosclerosis HDL transports CHOLESTEROL excess from arterial walls in the liver for removal from the body. in pathological conditions changing protein and lipid composition of plasma. Dyslipidemia, violation of insulin resistance, inflammation, infection, GCC can degrade normal HDL biological activity. In the structure of HDL3 acid esters are reduced apoA1, paraoksonazy1, lecitinholesterinaciltransferaz. Increases the level of TENGE. Reduced antioxidant and anti-inflammatory activity. Fig. 2 the main functions of HDL (antioxidant, , antithrombotic, antiishemia, antidiabetic) Fig. 3. Paccounts migration stimulation of macrophages, cholesterol HDL ingibirunt inflammatory Endothelial Activation and promotes jendotelialnomu recovery. About BA effect depend on the production of NO endothelium. In addition, HDL turns out Yu t antiapoptoticheskoe and antithrombotic effect. It was established that the level of HDL-C does not depend on the function of macrophage CHOLESTEROL outflow, and cannot be a marker of cardiovascular diseases (CVD). Individuals with genetically deterministic high levels of HDL are observed decrease in cardiovascular disease (Benjamin Voight, Philadelphia, online May 16, 2012, the Lancet). Asiamen have the highest incidence of ischemic heart disease, despite the fact that almost half of them lifelong adhere to vegetarianism. When building features 30-year survival among men, 40-59 years of credible the greatest survival rate is set at a level of HDL-C 1.7 mmol/l, but not above (Menschikov, a.a., 2013, Russian Federation). In most Japanese epidemiological studies [12] does not establish a link between strokes and high levels of total CHOLESTEROL. L people with exceptionally high levels of HDL cholesterol have increased rather than decreased risk of death from cardiovascular disease, cancer and other causes (Madsen et al . ). In meta-19 cohort studies [13] the level of total CHOLESTEROL was back hydraulicYong mortality from respiratory and gastrointestinal diseases, most of whom havewhether infectious origin . As a result of experiments on rodents back in 1996 year is set to rise after declining cancer cases total cholelesterol [14]. In individuals with Familial Hypercholesterolemia proved to be below the death rate from cancer [15]. The available evidence from randomized controlled studies show that replacing saturated fat linoleic acid effectively reduces the level of cholesterol in serum, but does not confirm the hypothesis that this leads to a decreased risk of death from ISCHEMIC heart disease or from all causes. The results of The Minnesota Coronary Experiment [11] complement the growing evidence that the incomplete publication of data contributed to the revaluation of benefits and underestimating the potential risks replacing saturated fats in the diet with vegetable oils rich in linoleic acid. The problem is that cardiovascular events more often develop in coronary arteries in areas of less than 70% lumen stenosis, as well as outside them. Diagnosis and treatment of these patients is difficult hidden atherosclerosis and low over the result of the stress tests for ISCHEMIC heart disease. Fig. 4. Treatment and prevention of coronary atherosclerosis (http://dx.doi.org/10.1136/bjsports-2016-097285 ). Research TRIUMPH and IHCS [5]. And zuch alas the subclass relationship HDL CHOLESTEROL (HDL-C) prediction of secondary prevention ISCHEMIC heart disease. Methods. From two cohorts: TRIUMPH study surveyed 2465 patients with acute myocardial infarction; IHCS study surveyed 2414 patient coronary angiographic method. All m patient am the basic subclasses of HDL_Cultracentrifugirovaniem. Stratified tertils HDL-C and two subclasses (HDL2-C, HDL3-C) . Patients were middle-aged (TRIUMPH: 58.2 ± 12.2 years; IHCS: 62.6 ± 12.6 years). Ba majority of them were womendistricts (TRIUMPH: 68.0%; IHCS: 65.5%). In triale IHCS were lower than values HDL-C (34.6 ± 10.1 mg/dL) compared with the TRIUMPH (40 ± 10.6 mg/dL). the proportion of HDL3-C was 3/4 > of HDL-C (coefficient3HDL-C/HDL-C was 0.78 ± 0.05 in both cohorts). The results of the For 2 years of observation. in a study of TRIUMPH mortality amounted to 226 cases (9.2%). For 5 years of observation of myocardial infarction mortality IHCS established among 401 patients (16.6%). Event dependencies is not installed with the levels of HDL-C , and HDL2-c. in contrast, low HDL tertil3-(C) reliably associated in each cohort of more than 50% of high risk. In triale TRIUMPH mortality correlation with HDL3-C was HR% CI 1.57; 95, 1.13-2.18 ; in study IHCS for mortality from myocardial infarction HR: 1.55; 95% CI, 1.20-2.00). Figure. 5. Skorrektirovann haunted spline-curve parameters HDL in Association with foresight Zom mortality and mortality from myocardial infarction. On OS Xand gives Hena parameter values of HDL-c and on Y-OSand Natasha Hena predictors of mortality through 2 years in TRIUMPHas well as smertnostb from myocardial infarction through 5 years in the IHCS after adjustment all curves. The dashed lines show the 95% confidence interval. (A) in the case of HDL-C, (in) -with HDL2, (c) HDL3-with. * Results are compatible for models 1, 2, and 3. Model 1 was without adjustments in both groups. Model 2 has been adjusted by GRACE score in TRIUMPH, and by age and sex in the IHCS. In only s TRIUMPH and IHCS [5]. 1. The results of the study, supplemented by biologic-epidemiologic and clinic proven materials give the right Select subclass HDL3 as the main risk marker. 2. Conducting secondary1st preventive, account should be taken of the increased risk for long-term hard clinical events related to lowerthem level HDL3-C . This does not apply to the values of HDL2-C or HDL-C. 3. The obtained results underscore the importance of separation of HDL on subclasses for risk stratification. In study GISSI - HF [4] found a significant reduction in LDL CHOLESTEROL level through 3 years of treatment with rozuvastatin. However, the drug does not improve clinical performance. Has not been explained by the absence of differences in respect of primary and secondary endpoints. Appointment of patients with CORONARY heart disease fibrate and Nicotinic Acid [6] increases the concentration of HDL, but, paradoxically, not reduces mortality. Application of RVX-280 on the therapy increased HDL on Statins 10.9%, lowered LDL by 16% but did not affect the frequency of cardiovascular complications. There are reports that the use of niacin boosts HDL, but reliably does not improve cardiovascular risk statistics ( Sekar Kathiresan. Massachusetts General Hospital, Boston ). The study of FIELD assignment fenofibrata at a dose of 200 mg/day for a period of 5 years for patients with diabetes mellitus type 2 significantly reduced the incidence of cardiovascular events, but only slightly increased by 2% HDL-C.he result was received in triale VA - HIT after gemfibrozils treatment. In test of The ACCORD Study Group tested the hypothesis that the use of fenofibrata to improve HDL-C plasma and plasma triglyceride reduction in patients with type 2 diabetes already receiving simvastatinom therapy will lead to additional cardio - vascular benefits compared to therapy one simvastatinom. primary outcome frequencies, however, does not differ between fenofibrata and reliably placebo during years of treatment and observation 4.7 [8]. Dalcetrapibs Drug in patients with diabetes mellitus has increased the concentration of CS HDL-C by 31% compared with placebo. SETR Inhibitors [7] significantly increase HDL levels, but did not significantly affect the cardiovascular events. Study of CETP-inhibitors give conflicting results. So in study ILLUMINATE therapy with torcetrapib, despite a significant increase in the level of HDL on 71% and reduce LDL by 24% conjured up with increasing frequency on CVD 25% and overall mortality at 58 percent. Another representative of this group drugs-dalsetrapib-dal-study OUTCOMES in patients recently undergoing acute coronary syndrome (Oaks), resulted in an increase in the concentration of HDL CHOLESTEROL in the blood, but did not differ from placebo on the incidence of primary endpoints (death from CHD, nonfatal acute myocardial infarction, ischemic stroke, unstable angina, etc.). Figure 6. (1) CETP penetrates into HDL. (2) education with both ends of the CETP. (3) the pores with a cavity in the CETP, forming a channel for the transfer of cholesterol, (4) that leads to a decrease in HDL. (Illustration Gang Ren/Berkeley Lab.) Research findings ILLUMINATE and dal-OUTCOMES suggest that the hypothesis on the advisability of increasing levels of HDL CHOLESTEROL to combat atherosclerosis has no today real evidence, therefore, search for similar drugs is meaningless. Thus, the main goal of therapy, corrective level of lipids in the blood, still is lowering the level of LDL CHOLESTEROL in the blood. currently, Statins (atorvastatin, rosuvastatin) superior to all other classes of lipid means for reducing the level of lipid profile. Conclusion. Variety of classes due to the heterogeneity of the HDL LEVELS of physical, chemical, functional HDL particles settings. Biological activity of HDL is deterministic composition of proteins and lipids. LPVP3 have expressed by antiatherogenic properties. However, there has been a transformation of pathological States of particles of HDL and loss of natural metabolic rate. CHS level of HDL is associated with lots of HDL2, HDL3, is a negative prognostic factor. HDL dysfunction leads to atherogen damage vessels. Increased level HDL with vazoprotektornymi properties-task for future therapy.
No one understands that it is actually necessary to determine in a patient not high-density cholesterol, but the absolute amount of high-density particles. Thanks
