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Condition of the process of apoptosis in the human population with asymptomatic hyperuricemia.


Asymptomatic hyperuricemia (AH) according to the population investigations is found in 28% of people (Malyavskaya, Lebedev, Ternovskaya, 2007; Filippatos, Ahmed, Gladden et al., 2011) and in 54%-60% of patients not only with the reduced, but also with the saved left ventricular ejection fraction (Larina, Bart, Larin, Donskov, 2013). Moderate hyperuricemia (MH) is the most often considered as biologically inactive condition (Nasonov, 2008).

At the same time, some investigators MH, including AH refers to the independent forming factors of metabolic syndrome (MS) (Wasserman, Shnell, Boursi, Gurner-Gur, 2010; Larina, Bart, Brodskiy, 2011). In patients with MS the development risk of cardiovascular diseases (CVD) and death reaches up to 75% (Fillipov, Khandjan, Solodukhin, 2008), development frequency of acute myocardial infarction (AMI) makes up to 10% and the development risk of heart failure (HF) makes up to 20-35% (Larbe, Torres, Torro et al., 2009). Among cases in the development of MH and AH as starting device of CVD it is considered the role of the endothelial dysfunction (ED) (Fillipov, Khandjan, Solodukhin, 2008). ED is conditioned by disorders of nitric oxide (NO) formation by the endothelial cells and disorders of vasodilatation and other functions which performed by NO (Markov, 2005). The role of NO as a development factor of MH is actively discussed in the literature (Polovitkina, Oshepkova, Dmitriev, Titov, 2011). Its effect in supporting of the high level of uric acid (UA) NO is realized through the mechanisms of apoptosis (Corry, Eslami, Yamamoto et al., 2008). In the physiological concentrations NO inhibits apoptosis which play a key role in the regulation of the activity of cardio-vascular system. The general antiapoptic effect of NO could be mediated by the several mechanisms such as nitrolysation and inactivation of caspase, blocking delivery of prokaspase-9 to Apaf-Iapostome, activation of Bel-2 and Bel-XL with following inhibition of cytochrome C release from mitochondrion (Najafipur, Dolgov, Orlova, Cormer, Shevchenko, 2007).

The mechanisms of apoptosis could be realized through Fas (CD95)/Fas ligand system. Progression of HF and death of cardiac hystiocytes have been connected with the activity of Fas-induced apoptosis. It is considered that the soluble types of Fas-mediated markers of apoptosis--sFas protein and its ligand sFasl--are the markers which could allow us to evaluate the significance of apoptosis process in patients with CF. It has been established that CD95 (Apo-I, Fas-antigen) represents superficial glycosytated protein of the cells membrane which belong to the group of tumor necrosis factor (TNF) / receptor of the nerve growth factor. Fas are expressed on the surface of B- and T-lymphocytes, cells of the different tumors and also on the surface of the some other cells of the human body.

The increasing expression of Fas protein on the cells' surface induces interferon and TNF[alpha], and also activation of lymphocytes. Natural substance connected with Fas protein its ligand (FasL) belongs to the TNF[alpha] group (Poradin, Salmasi, Cazimirskiy, 2006). Binding Fas with FasL or with antibodies against Fas lead to the trimerisation of Fas and the following interaction with proteins which forms DISC complex (death induced signal complex) which initiate processes of apoptosis (Najafipur, Dolgov, Orlova, Cormer, Shevchenko, 2007). Disorders of apoptosis could be reinforced by increasing of concentration NO during the activation of the biological systems. A number of authors consider that the most proapoptotic effects of NO belong to peroxynitrite ([ONO-.sub.2]) which forms in the reaction with superoxide ([O.sup.-.sub.2]). Concentration of NO in tissues increases due to activation of the pathological isoform of NOS--induced NOS (iNOS) which initiates suppression of macrophages starting up of apoptosis (Petrishev, Vasina, Lugovaya, 2008). Taking into consideration the importance of NOS and high level of UA in the realization of the process of apoptosis, development of MS and CVD, we should consider that in the human population with AH these processes are mediated by the mechanisms of changes in Fas (CD95) / Fas-ligand system.

The aim of investigation--to evaluate of the activity level of NOS and soluble forms Fas markers--mediated apoptosis (sFas and sFasL) in patients with AH and its relationships with concentration of UA in the blood.

Materials and methods

59 patients at the age 46.4[+ or -]3.49 years old were included in the investigation, including 17 patients (28.8%)--1 group with normal level of UA in the blood (254.2[+ or -]16.01 mmol/l), 22 patients (37.3%)--2 group with moderate level of UA in the blood (295.1[+ or -]15.83 mmol/l) and 20 patients (33.9%) with extremely high level of UA in the blood (up to 350.0[+ or -]17.85 mmol/l) Patients with the different level of UA were determined in the ambulatory level and fortuitousness during preventive investigations of people who joined to work.

The activity of the endothelial function was evaluated by the amount indexes of stable metabolites of NO (by the method of Golikov et al., 2004), activity of endothelial NOS (eNOS)--by the method of Sumbaev and Yasinskaya (2000), activity of iNOS and concentration of [ONO.sup.-.sub.2]--by the method of Komarin and Azimov (2005) in the blood serum.

At the same time the amount of factors which were able to regulate apoptosis of the cells -TNF[alpha] and soluble forms of Fas-ligands (sFasL) were determined in the blood serum with the use of immune-enzyme autoanalyzer with computer device AT-858 (LTD, China) with using of test-reagents of "Bender MedSystem" firm (Austria). Statistic processing of the data was performed by the use of the SPSS 11.5.0 program. All values were presented as M[+ or -]m form. The differences at P<0.05 values were considered as statistically significant.

Results and discussion

Expression on the membrane structures by the superficial CD95 molecules (sFas and sFasL) potentiates cells' readiness to introduction to apoptosis as direct interaction of them with these ligands is one of the leading mechanisms of launching of apoptosis. Regulation mechanisms of apoptosis are diverse and can act in the different levels. Cytokines, growth factors and other cells incoming to the microenvironment of cardiac hystiocytes take part in regulation process of apoptosis. Interaction of Fas- FasL or TNFa molecules could be the signal to the development of apoptosis. In any case regulation of apoptosis has been carried out through genes' activation either initiating apoptosis, such as p53 or inhibiting cells' destruction, such as bcl-2.

The analyses of the received data have been showed that in the investigated groups the average level of sFas (inhibitor of apoptosis) with increasing concentration UA in the blood has been dynamically decreased. So, in comparison with the 1st group in patients of the 2nd group sFas was lower in 19.3% (P<0.05), and in patients of the 3rd group it was lower in 34.3% (P<0.01). In the 3rd group of patients the amount of sFas was lower than in the 2nd group in 18.6% (P<0.05). At the same time sFasL (inhibitor of apoptosis) and also cytokine TNFa in the blood with the increasing level of UA in patients with AH have been dynamically increased. In the comparison with the 1st group in the investigated group (the 2nd group) the level of sFasL was higher in 30% (P<0.01), and the level of TNF[alpha] was higher in 19.5% (P<0.05), and accordingly in the 3rd group of patients these levels were high in 50.0% (P<0.001) and in 46.2% (P<0.001). The ratio of the levels sFas and sFasL (sFas/sFasL) in patients of the 1st group were 14.0[+ or -]0.68, and in the 2nd and 3rd groups of patients it was accordingly 8.7[+ or -]0.38 and 6.1[+ or -]0.33.

At the same time with the change of factors regulating apoptosis it has been revealed significant changes in the rate characterizing of ED. Thus, the dynamic reduction activities ofNO and eNOS occurred against a background of increasing the activity of inducible NOS and concentration of [ONO-.sub.2] (Table 1). In patients of the 2nd and 3rd groups level of NO was reduced in 17.6% (P<0.05) and 25.3% (P<0.01), eNOS--in 15.9% (P<0.05) and 22.5% (P<0.02), and activity of iNOS and content of [ONO-.sub.2] were high in 18.2 and 18.6% (P<0.05), and also accordingly in 40.0 and 44.2% (P<0.01) in the 3 group of patients.

At the same time, it has been determined a clear relationship between the increased levels of sFasL and iNOS, [ONO-.sub.2], TNF[alpha]: in the 1st group of patients--r= 0.55-0.63 (P <0.05), in the 2nd group of patients--r=0.69-0.71 (P<0.01) and in the 3rd group of patients r=0.76-0.82 (P<0.01), and reverse relationship between levels of sFas: with indicators NO, eNOS and TNFa--r =-0.48-0.60 (P <0.05) during the assessment of relationship in the 1st group of patients, r--0.59-0.68 (P<0.01)--in the 2nd group of patients and r-- 0.67-0.78 (P<0.01) in the 3rd group of the investigated patients.

During the analyses of relationship of the levels of UA indexes in the blood with factors regulating apoptosis and activity of NOS it has been established that as concentration of UA is high, as high its correlation index. Thus in the 1st group of patients relationship of UA (r) with sFasL, iNOS, [ONO-.sub.2], TNF[alpha] was within from 0.48 to 0.52 (P<0.05), in the 2nd group of patients it was within from 0.58 to 0.70 (P<0.01), in the 3rd group of patients it was within from 0.68 to 0.83 (P<0.001), and reverse relationship with the indexes of sFas, NO and eNOS--r=- from 0.60 to 0.65 (P<0.05), from 0.73 to 0.81 and from 0.79 to 0.85 accordingly due to investigated groups.

So, the carried out investigations showed that the action balance of proapoptotic and apoptotic signals in the blood serum in AH have been shifted to the initiation of the metabolic processes and to the accelerated apoptosis. This, perhaps, has been determined in patients with AH development of CVD, readiness of cardiac hystiocytes, system of central hemodynamic and heart to the development of cardiovascular disorders, high development risk of HF and AMI. At the same time our investigation has demonstrated that in AH it is not only accelerated apoptotic processes, but also it is increased readiness to entry of the immune system to apoptosis. Perhaps, signal mechanisms from the beginning of forming apoptotic reactions in AH are universal and are not depended on the tissue localization. Perhaps in the peripheral blood the influence balance of the regulation factors such as expression of sFasL and reduction of sFas has shifted to the side of signal intensification in order to accelerated apoptosis by the factors of the immune system. This is also facilitated by ED, reducing NO, eNOS, iNOS activation and the formation of a cytotoxic compound ONO-2. Creating conditions are likely to be unfavorable factor for the normal functioning of cardiac hystiocytes that consequently increases their readiness to develop of CVD. However, high levels of UA over the long time period, presumably determine conditions for reducing the activities of eNOS and NO in the endothelium. Adequate in this process is the increased activity of iNOS to compensate the insufficient amount of NO and the excess of which goes to the formation of [ONO-.sub.2]. Apparently, the increased activity of iNOS and formation of [ONO-.sub.2] create the conditions for amplification proapoptotic processes, favor to rise of the tension of the immune system that we have considered as a reaction of the body in patients with AH directed to the elimination of activated by apoptosis systems and prevent the development of systemic vascular lesions. Revealed increasing regularity due MUA in the blood serum with soluble forms of apoptosis sFasL and sFas with a degree of balance disorders NOS, increasing TNF[alpha] in patients with AH suggesting their importance in the development mechanisms of cardiovascular diseases. It has principal significance for prognosis and elaboration of the preventive measures of prevention and therapeutic approaches of correction of the determined abnormalities in the purine metabolism from accepted norms of UA.


On the basis of the received results we could formulate the following conclusion.

In patients with AH the increase UA level in the blood leads to increasing in the levels of sFasL, iNOS, [ONO-.sub.2], TNF[alpha], and decreasing in the levels of sFas, NO and eNOS. Values of the increased levels of UA in the blood serum have a clear direct correlation with sFasL - mediated apoptosis, iNOS, [ONO-.sub.2] and TNF[alpha] and an inverse relationship with sFas, NO and eNOS. A direct and strong correlation of sFasL is found with iNOS, [ONO-.sub.2] and TNF[alpha] and its reverse correlation with sFas, NO and eNOS. Meanwhile, sFas inverse correlation is established with iNOS, [ONO-.sub.2] and TNF[alpha] and its direct strong correlation with NO and eNOS. The obtained data of the reduction integral index of sFas/sFasL in dynamic growth level of UA in the blood represent decreasing level of sFas apoptosis inhibitor and increasing level of apoptosis inducer such as sFasL, sFas/sFasL.

Revealed the presence of correlation between the dynamic increase of UA, indicators regulation of apoptosis, NOS and TNF[alpha] demonstrates the importance of AH in the reducing the adaptive protection of the body and increasing the risk of cardiovascular disorders.


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E.N. Tashkenbaeva, A.L. Alavi, D.Kh. Togaev, F.Sh. Kadirova

Samarkand State Medical Institute, Samarkand Branch of RSCEMC

Source: E.N. Tashkenbaeva, A.L. Alavi, D.Kh. Togaev, F.Sh. Kadirova, 2014. "Condition of the process of apoptosis in the human population with asymptomatic hyperuricemia", Medical and Health Science Journal, Vo.15(2), pp.39-43, DOI: 10.15208/mhsj.2014.06

Groups of
patients     [TNF.sub.a] ng/ml       sFas, ng/ml

1 group      19.5 [+ or -] 0.94   1.4 [+ or -] 0.08

2 group      23.3 [+ or -] 1.03   1.13 [+ or -] 0.05

3 group          * [DELTA]            * [DELTA]
n=20         28.5 [+ or -] 1.34   0.92 [+ or -] 0.04

Groups of
patients        sFasL, ng/ml           sFas/sFasL

1 group      0.10 [+ or -] 0.001   14.0 [+ or -] 0.68

2 group      0.13 [+ or -] 0.007   8,7 [+ or -] 0,38

3 group           * [DELTA]            * [DELTA]
n=20         0.15 [+ or -] 0.011   6.15 [+ or -] 0.33

Groups of           NO,                 cNOS
patients          mcmol/I         mcmol / min / I

1 group      9.1 [+ or -] 0.32   13.8 [+ or -] 0.63

2 group      7,5 [+ or -] 0,29   11,6 [+ or -] 0,47

3 group          * [DELTA]           * [DELTA]
n=20         6.8 [+ or -] 0.32   10.7 [+ or -] 0.33

Groups of           iNOS              ON[O2.sub.2]-
patients       mcmol / min / I           mcmol/I

1 group      0.22 [+ or -] 0.011   0.43 [+ or -] 0.022

2 group      0,26 [+ or -] 0,010   0.51 [+ or -] 0.018

3 group           * [DELTA]             * [DELTA]
n=20         0.31 [+ or -] 0.014   0.62 [+ or -] 0.032

Note: *--P < 0.05 as regards to the 1st group.
[DELTA]--P < 0.05 as regards to 2nd group.
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Author:Tashkenbaeva, E.N.; Alavi, A.L.; Togaev, D.Kh.; Kadirova, F.Sh.
Publication:Medical and Health Science Journal
Article Type:Report
Date:Apr 1, 2014
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