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Content of S100b Protein, HLDF24 Peptide and Autoantibodies to These Factors as Potential Biomarkers for Arterial Hypertension in Blood Serum of Healthy People M. A. Gruden, E. I. Elistratova, M. V. Kudrina, V. P. Karlina*, I. S. Deryabina*, I. M. Semenova*, V. M. Ryzhov*, and V. V. Sherstnev
Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 156, No. 10, pp. 409-412, October, 2013 Original article submitted August 6, 2012 The content of S100b protein, HLDF24 peptide, and autoantibodies to these factors in blood serum was measured in healthy individuals (35-64-year-old men and women) with various levels of “normal” BP. Significant differences in the amount of these molecular factors were found in individuals with various categories of BP. We revealed age-related and gender differences in the content of molecular factors in the serum. Our results indicate that variations in the concentration of S100b, HLDF24, and autoantibodies to these factors in blood serum from adult people can serve as a reliable criterion for the risk of arterial hypertension. Key Words: biomarkers; essential hypertension; S100b protein; HLDF24 peptide; autoantibodies Much attention is paid to the search for new biomarkers of arterial hypertension (AH) and prognosis for its progression. AH is one of the most common diseases in able-bodied population of Russia and most countries in the world. AH is a major risk factor for cardiovascular and cerebrovascular diseases, which determines the necessity of these studies [1,5,8,11]. Neurospecific protein S100b, human leukemia differentiation factor (HLDF), and autoantibodies (AB) to these compounds in blood serum of patients belong to molecular factors that hold much promise as biomarkers for the risk of AH. Clinical and experimental studies showed that these molecular factors are involved in the mechanisms of AH and acute or chronic disturbances in cerebral blood circulation of the hypertensive genesis. The concentrations of S100b and AB to S100b in blood serum reflect functional activity of the nervous system. The concentration of P. K. Anokhin Research Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow; *Medical and Sanitary Hospital No. 170, Federal Medical and Biological Agency of Russia, Korolev, Russia. Address for correspondence:
[email protected]. M. A. Gruden
HLDF protein, its peptide fragment HLDF24 (retaining hemodynamic properties of this factor), and AB to these factors serves as a criterion for cardiovascular function [2-4,6,9,10]. Studies of S100b protein, HLDF24 peptide, and AB to these compounds as biomarkers for the risk of AH should be performed taking into account the age norm for the average content of these molecular factors in blood serum. Moreover, it is necessary to evaluate the relationship between the content of study factors, sex, age, and level of BP. Our study was performed to solve these problems. Here we measured the concentrations of S100b protein, HLDF peptide, and idiotypic AB to these factors in blood serum from healthy volunteers of different sex, age, and BP level.
MATERIALS AND METHODS A routine prophylactic medical examination allowed us to derive the group of conditionally healthy people (N=72, mean age 45±11 years). It was composed from men (N=31) and women (N=41) of the following
0007-4888/14/15640426 © 2014 Springer Science+Business Media New York
M. A. Gruden, E. I. Elistratova, et al.
age subgroups: 35-44 years (13 men and 12 women) and 45-64 years (28 men and 10 women). According to the Russian recommendations on the diagnostics and therapy of AH [1], patients of both subgroups were divided into the following BP categories: “optimal” category (systolic BP [SBP] / diastolic BP [DBP] 150/99 mm Hg, N=11). Serum samples of the peripheral blood were obtained from the cubital vein. The content of S100b protein (ng/ml) was measured routinely by ELISA. The concentrations of HLDF24 peptide (ng/ml) and idiotypic AB to both factors (titer) were estimated using original test systems [2,6]. The results were analyzed by nonparametric analysis of variance (Kruskal–Wallis test) and subsequent evaluation of between-group differences by Mann–Whitney U test (Statistica 7.0 software). The critical level of a statistical significance (p) in null hypothesis testing was 0.05. The data are presented as M±m, where M is arithmetic mean; and m is standard error of the mean.
RESULTS In patients with “optimal”, “normal”, “high-normal”, and “borderline” categories of BP, the mean concentrations of HLDF24 peptide were 67.2±21.8, 91.4±31.9, 94.9±30.3, and 121.0±40.8 ng/ml, respectively. The mean concentrations of S100b protein in these patients were 63.80±24.69, 78.1±20.1, 73.9±17.8, and 79.5±20.3 ng/liter, respectively. The mean titers of anti-HLDF24 AB in blood serum from patients with the
427 “optimal”, “normal”, “high-normal”, and “borderline” categories of BP were 1:80.5±1:15.9, 1:60.5±1:16, 1:207.3±1:32, and 1:225.5±1:38.1, respectively. The mean titers of anti-S100b AB in these patients were 1:104.0±1:16.5, 1:135.5±1:12.5, 1:129.5±1:16.0, and 1:126.5±1:10.4, respectively. We studied the relationship of S100b protein concentration in blood serum with the age, sex, and BP categories. S100b content in men belonging to “normal” BP category and aging 35-44 years was significantly higher than in women of the same age and BP level. S100b concentration in men of this age belonging to “optimal” BP category was higher than in women with “high-normal” BP. S100b content was elevated in 35-44- and 45-64-year-old men of with “normal” BP (vs. men of the same age with “optimal” BP), as well as in 34-44-year-old men of “normal” BP category (vs. men of the same age with “borderline” BP). S100b concentration in women aging 45-64 years and belonging to “borderline” BP category was higher than in women of the same age with “optimal” BP (Fig. 1). The titer of anti-S100b AB in blood serum was measured in patients of various sex, age, and BP categories. The titer of these AB in men aging 45-64 years with “high-normal” BP was higher than in men of the same age with “optimal” BP. The titer of antiS100b AB in 35-44-year-old men with “normal” BP exceeded that in men of the same age with “optimal” and “borderline” BP and women of the same age with “optimal” and “normal” BP (Fig. 3). HLDF24 content in men of various age groups with “optimal” BP was much lower than in women of the same age and BP categories. Peptide concentration was elevated in 45-64-year-old men with “borderline”
Fig. 1. S100b protein concentration in blood serum of healthy women (light bars) and men (dark bars) of different age and BP categories. p0.05 in comparison with: *45-64-year-old men with “optimal” BP; +35-44-year-old men with “optimal” and “borderline” BP; o35-44-year-old women with “high-normal” and “optimal” BP; x45-64-year-old women with “optimal” and “high-normal” BP.
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Fig. 2. HLDF24 peptide concentration in blood serum of healthy women (light bars) and men (dark bars) of different age and BP categories. p0.05 in comparison with: *women of the same age with “optimal” BP; +women and 35-44-year-old men with “optimal” and “high-normal” BP; o35-44-year-old women with “high-normal” BP; xmen of the same age with “optimal”, “normal, and “high-normal” BP; #35-44-year-old men with “borderline” BP.
Fig. 3. Titer of AB to HLDF24 and S100b in blood serum of healthy women (light bars) and men (dark bars) of different age and BP categories. Ordinate: titer (1:n, where n is the final dilution of blood serum from a patient yielding positive reaction in ELISA)) of AB to HLDF24 (1) and S100b (2). p0.05 in comparison with: *35-44- and 45-64-year-old men with “optimal”, “normal”, and “borderline” BP; +35-44- and 45-64-year-old women with “optimal” and “normal” BP; o45-64-year-old women with “optimal” and “normal” BP; x35-44-year-old men with “high-normal” BP; &45-64-year-old men with “borderline” BP; ^45-64-year-old women with “optimal” and “normal” BP; #men and 35-44-yearold women with “optimal”, “normal”, and “borderline” BP.
BP (vs. younger men of the same BP category), as well as in 35-44-year-old women of “high-normal” BP category (vs. 45-64-year-old women with the same level of BP). HLDF24 concentration in 35-44-yearold women with “high-normal” BP category was significantly higher than in men and women of the same age with “optimal” and “normal” BP. Serum peptide content in 45-64-year-old men with “borderline” BP was higher than in men of the same age belonging to other categories of BP (Fig. 2). The titer of anti-HLDF24 AB in 45-64-year-old men with “high-normal” BP was much higher than in younger men of other BP categories. The titer of anti-
HLDF24 AB was elevated in 35-44-year-old women with “high-normal” BP, as well as in 45-64-year-old women with “borderline” BP (vs. women of the corresponding age groups with “optimal” and “normal” BP). The titer of anti-HLDF24 AB in 35-44-year-old women with “high-normal” BP was much higher than in men of the same age group and BP category. The titer of anti-HLDF24 AB was elevated in 45-64-yearold women with “borderline” BP (vs. men of the same age group and BP category). These results allow us to make two conclusions. First, the content of these molecular factors in blood serum significantly increases in men and women with
M. A. Gruden, E. I. Elistratova, et al.
“high-normal” and “borderline” BP (i.e., in people with the highest level of BP). The concentration of S100b protein, HLDF24 peptide, and AB to these factors in patients with “normal” BP is higher than in people of “optimal” BP category. The content of molecular factors in these people does not differ from the mean values. The level of BP is a major factor, which determines the prognosis of AH and cardiovascular diseases. The elevation of BP by 20/10 mm Hg above 115/75 mm Hg is accompanied by a 2-fold increase in the risk for cardiovascular diseases. In Canada and USA, the categories of “normal” and “high-normal” BP are considered as “pre-hypertension”. Second, significant variations in the content of molecular factors are often observed in 55-64-year-old people. Published data show that the incidence of AH increases with age. For example, the incidence of this disease in 45-64-year-old patients is 2-fold higher than in people aging 35-44 years [1,7]. Our results indicate that these molecular factors hold much promise as new biomarkers of AH. Variations of their content in blood serum from conditionally healthy men and women of mature age can serve as a reliable criterion for the risk of AH.
429 This work was supported by the Russian Humanitarian Scientific Foundation (project No. 12-06-00709).
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