Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension
In addition to the key role in biosynthesis some aminoacyl-tRNA synthetases provide non-canonical functions. Particularly, separated fragments of tyrosyl-tRNA synthetase (TyrRS) involved into angiogenesis and inflammation. Meanwhile, the vascular inflammation and endothelial dysfunction are central...
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Інститут молекулярної біології і генетики НАН України
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| Цитувати: | Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension / M.Yu. Grom, L.F. Yakovenko, V.M. Granich, A.S. Dobrohod, O.O. Torbas, A.D. Radchenko, Yu.M. Sirenko, L.L. Sidorik, A.I. Kornelyuk // Вiopolymers and Cell. — 2015. — Т. 31, № 4. — С. 255-263. — Бібліогр.: 47 назв. — англ. |
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Grom, M.Yu. Yakovenko, L.F. Granich, V.M. Dobrohod, A.S. Torbas, O.O. Radchenko, A.D. Sirenko, Yu.M. Sidorik, L.L. Kornelyuk, A.I. 2019-06-12T12:26:46Z 2019-06-12T12:26:46Z 2015 Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension / M.Yu. Grom, L.F. Yakovenko, V.M. Granich, A.S. Dobrohod, O.O. Torbas, A.D. Radchenko, Yu.M. Sirenko, L.L. Sidorik, A.I. Kornelyuk // Вiopolymers and Cell. — 2015. — Т. 31, № 4. — С. 255-263. — Бібліогр.: 47 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.0008E9 https://nasplib.isofts.kiev.ua/handle/123456789/152568 577.27; 616.12-008.331.1 In addition to the key role in biosynthesis some aminoacyl-tRNA synthetases provide non-canonical functions. Particularly, separated fragments of tyrosyl-tRNA synthetase (TyrRS) involved into angiogenesis and inflammation. Meanwhile, the vascular inflammation and endothelial dysfunction are central characteristics of the pathogenesis of essential hypertension (EH). The latest studies highlight a role of antibodies in physiopathology of EH. Aim. We had investigated the full-length TyrRS and its domains as autoantigens in sera of the persons with EH (n = 25), the healthy individuals with family history of the pathology (n = 12), and in the control group of healthy subjects (n = 32). Methods. The recombinant TyrRS and its separated domains coupled with His-tags and generated by Escherichia coli were purified by chromatography on Ni-NTA-agarose. The levels of specific autoantibodies (aAbs) in sera of volunteers were measured by ELISA and confirmed in an immunoblotting assay. Results. Some subjects with elevated levels of aAbs against the full-length enzyme were detected in the cohort studies. 52 % of the persons with EH as immunoreactive against miniTyrRS (p < < 0.001) and 50 % against CTD (p = 0.002) were identified. In 50 % of the healthy individuals with family history of EH (p = 0.037) the levels of anti-CTD aAbs were elevated. Conclusions.The increased levels of aAbs against miniTyrRS and CTD in sera of the persons with EH potentially may be used as a prognostic marker of the disease severity or therapy effectiveness. Moreover, the immunoreactivity of healthy individuals with family history of EH against CTD may be an early marker of hypertension. Окрім ключової ролі у біосинтезі білка певні аміноацил-тРНК синтетази виконують також неканонічні функції. Зокрема окремі домени тирозил-тРНК синтетази залучені до ангіогенезу та запальних реакцій. Тим часом, судинні запалення і дисфункція ендотелію є центральними характеристиками патогенезу гіпертонічної хвороби (ГБ). Останні дослідження підкреслюють роль антитіл в патофізіології ГБ. Мета. Дослідити повнорозмірну TyrRS і її окремі домени як аутоантигени в сироватках осіб з ГБ (n = 25), у здорових осіб з сімейною історією патології (n = 12), і в контрольній групі здорових осіб (n = 32). Методи. Рекомбінантна TyrRS і її окремі домени, пов'язані з His-теґами, експресувалися в клітинах E. coli, та очищалися хроматографією на Ni-NTA-агарозе. Рівні специфічних аутоантитіл (aAbs) в сироватці добровольців були виміряні методом ІФА та підтверджені в імуноблотингу. Результати.Некоторие пацієнти з підвищеним рівнем aAbs проти повнорозмірного ферменту були виявлені в когортних дослідженнях. 52 % осіб з ГБ були ідентифіковані як імунореактивні проти miniTyrRS (р < 0,001) і 50 % проти CTD (р = 0,002). У 50 % здорових осіб з сімейною історією ГБ (р = 0,037) рівні анти-CTD aAbs були підвищені. Висновки. Збільшення рівнів aAbs проти miniTyrRS і CTD у сироватці осіб з ГБ потенційно може бути використане як прогностичний маркер ступеня тяжкості захворювання та ефективності терапії. Крім того, імунореактивність проти CTD здорових людей з сімейною історією ГБ може бути раннім маркером гіпертонії. Кроме ключевой роли в процессе биосинтеза белка ряд аминоацил-тРНК синтетаз также исполняют, так называемые, неканонические функции. В частности, отдельные домены тирозил-тРНК синтетазы вовлечены в ангиогенез и воспалительные реакции. Между тем, сосудистой воспаление и дисфункция эндотелия являются центральными характеристиками патогенеза гипертонической болезни (ГБ). Последние исследования подчеркивают роль антител в патофизиологии ГБ. Цель. Исследовать полноразмерную TyrRS и ее отдельные домены как аутоантигены в сыворотках лиц с ГБ (n = 25), у здоровых лиц с семейной историей патологии (n = 12), и в контрольной группе здоровых лиц (n = 32). Методы. Рекомбинантная TyrRS и ее отдельные домены, связанные с His-тегами и экспрессированные в E. coli, очищали хроматографией на Ni-NTA-агарозе. Уровни специфических аутоантител (aAbs) в сыворотке добровольцев были измерены методом ИФА и подтверждены в иммуноблоттинге. Результаты.Некоторые пациенты с повышенным уровнем aAbs против полноразмерного фермента были обнаружены в когортных исследованиях. 52 % лиц с ГБ были идентифицированы как иммунореактивные против miniTyrRS (р < 0,001) и 50 % против CTD (р = 0,002). У 50 % здоровых лиц с семейной историей ГБ (р = 0,037) уровни анти-CTD aAbs были повышены. Выводы. Увеличение уровней aAbs против miniTyrRS и CTD в сыворотке у лиц с ГБ потенциально может быть использовано в качестве прогностического маркера степени тяжести заболевания и эффективности терапии. Кроме того, иммунореактивность против CTD здоровых людей с семейной историей ГБ может быть ранним маркером гипертонии. en Інститут молекулярної біології і генетики НАН України Вiopolymers and Cell Biomedicine Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension Аутоантитіла проти тирозил-тРНК синтетази та її окремих доменів при гіпертонічній хворобі Аутоантитела против тирозил-тРНК синтетазы и ее отдельных доменов при гипертонической болезни Article published earlier |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| title |
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension |
| spellingShingle |
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension Grom, M.Yu. Yakovenko, L.F. Granich, V.M. Dobrohod, A.S. Torbas, O.O. Radchenko, A.D. Sirenko, Yu.M. Sidorik, L.L. Kornelyuk, A.I. Biomedicine |
| title_short |
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension |
| title_full |
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension |
| title_fullStr |
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension |
| title_full_unstemmed |
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension |
| title_sort |
autoantibodies against tyrosyl-trna synthetase and its separated domains at essential hypertension |
| author |
Grom, M.Yu. Yakovenko, L.F. Granich, V.M. Dobrohod, A.S. Torbas, O.O. Radchenko, A.D. Sirenko, Yu.M. Sidorik, L.L. Kornelyuk, A.I. |
| author_facet |
Grom, M.Yu. Yakovenko, L.F. Granich, V.M. Dobrohod, A.S. Torbas, O.O. Radchenko, A.D. Sirenko, Yu.M. Sidorik, L.L. Kornelyuk, A.I. |
| topic |
Biomedicine |
| topic_facet |
Biomedicine |
| publishDate |
2015 |
| language |
English |
| container_title |
Вiopolymers and Cell |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| format |
Article |
| title_alt |
Аутоантитіла проти тирозил-тРНК синтетази та її окремих доменів при гіпертонічній хворобі Аутоантитела против тирозил-тРНК синтетазы и ее отдельных доменов при гипертонической болезни |
| description |
In addition to the key role in biosynthesis some aminoacyl-tRNA synthetases provide non-canonical functions. Particularly, separated fragments of tyrosyl-tRNA synthetase (TyrRS) involved into angiogenesis and inflammation. Meanwhile, the vascular inflammation and endothelial dysfunction are central characteristics of the pathogenesis of essential hypertension (EH). The latest studies highlight a role of antibodies in physiopathology of EH. Aim. We had investigated the full-length TyrRS and its domains as autoantigens in sera of the persons with EH (n = 25), the healthy individuals with family history of the pathology (n = 12), and in the control group of healthy subjects (n = 32). Methods. The recombinant TyrRS and its separated domains coupled with His-tags and generated by Escherichia coli were purified by chromatography on Ni-NTA-agarose. The levels of specific autoantibodies (aAbs) in sera of volunteers were measured by ELISA and confirmed in an immunoblotting assay. Results. Some subjects with elevated levels of aAbs against the full-length enzyme were detected in the cohort studies. 52 % of the persons with EH as immunoreactive against miniTyrRS (p < < 0.001) and 50 % against CTD (p = 0.002) were identified. In 50 % of the healthy individuals with family history of EH (p = 0.037) the levels of anti-CTD aAbs were elevated. Conclusions.The increased levels of aAbs against miniTyrRS and CTD in sera of the persons with EH potentially may be used as a prognostic marker of the disease severity or therapy effectiveness. Moreover, the immunoreactivity of healthy individuals with family history of EH against CTD may be an early marker of hypertension.
Окрім ключової ролі у біосинтезі білка певні аміноацил-тРНК синтетази виконують також неканонічні функції. Зокрема окремі домени тирозил-тРНК синтетази залучені до ангіогенезу та запальних реакцій. Тим часом, судинні запалення і дисфункція ендотелію є центральними характеристиками патогенезу гіпертонічної хвороби (ГБ). Останні дослідження підкреслюють роль антитіл в патофізіології ГБ. Мета. Дослідити повнорозмірну TyrRS і її окремі домени як аутоантигени в сироватках осіб з ГБ (n = 25), у здорових осіб з сімейною історією патології (n = 12), і в контрольній групі здорових осіб (n = 32). Методи. Рекомбінантна TyrRS і її окремі домени, пов'язані з His-теґами, експресувалися в клітинах E. coli, та очищалися хроматографією на Ni-NTA-агарозе. Рівні специфічних аутоантитіл (aAbs) в сироватці добровольців були виміряні методом ІФА та підтверджені в імуноблотингу. Результати.Некоторие пацієнти з підвищеним рівнем aAbs проти повнорозмірного ферменту були виявлені в когортних дослідженнях. 52 % осіб з ГБ були ідентифіковані як імунореактивні проти miniTyrRS (р < 0,001) і 50 % проти CTD (р = 0,002). У 50 % здорових осіб з сімейною історією ГБ (р = 0,037) рівні анти-CTD aAbs були підвищені. Висновки. Збільшення рівнів aAbs проти miniTyrRS і CTD у сироватці осіб з ГБ потенційно може бути використане як прогностичний маркер ступеня тяжкості захворювання та ефективності терапії. Крім того, імунореактивність проти CTD здорових людей з сімейною історією ГБ може бути раннім маркером гіпертонії.
Кроме ключевой роли в процессе биосинтеза белка ряд аминоацил-тРНК синтетаз также исполняют, так называемые, неканонические функции. В частности, отдельные домены тирозил-тРНК синтетазы вовлечены в ангиогенез и воспалительные реакции. Между тем, сосудистой воспаление и дисфункция эндотелия являются центральными характеристиками патогенеза гипертонической болезни (ГБ). Последние исследования подчеркивают роль антител в патофизиологии ГБ. Цель. Исследовать полноразмерную TyrRS и ее отдельные домены как аутоантигены в сыворотках лиц с ГБ (n = 25), у здоровых лиц с семейной историей патологии (n = 12), и в контрольной группе здоровых лиц (n = 32). Методы. Рекомбинантная TyrRS и ее отдельные домены, связанные с His-тегами и экспрессированные в E. coli, очищали хроматографией на Ni-NTA-агарозе. Уровни специфических аутоантител (aAbs) в сыворотке добровольцев были измерены методом ИФА и подтверждены в иммуноблоттинге. Результаты.Некоторые пациенты с повышенным уровнем aAbs против полноразмерного фермента были обнаружены в когортных исследованиях. 52 % лиц с ГБ были идентифицированы как иммунореактивные против miniTyrRS (р < 0,001) и 50 % против CTD (р = 0,002). У 50 % здоровых лиц с семейной историей ГБ (р = 0,037) уровни анти-CTD aAbs были повышены. Выводы. Увеличение уровней aAbs против miniTyrRS и CTD в сыворотке у лиц с ГБ потенциально может быть использовано в качестве прогностического маркера степени тяжести заболевания и эффективности терапии. Кроме того, иммунореактивность против CTD здоровых людей с семейной историей ГБ может быть ранним маркером гипертонии.
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0233-7657 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/152568 |
| citation_txt |
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension / M.Yu. Grom, L.F. Yakovenko, V.M. Granich, A.S. Dobrohod, O.O. Torbas, A.D. Radchenko, Yu.M. Sirenko, L.L. Sidorik, A.I. Kornelyuk // Вiopolymers and Cell. — 2015. — Т. 31, № 4. — С. 255-263. — Бібліогр.: 47 назв. — англ. |
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255
Biomedicine ISSN 0233-7657
Biopolymers and Cell. 2015. Vol. 31. N 4. P. 255–263
doi: http://dx.doi.org/10.7124/bc.0008E9
UDC 577.27; 616.12-008.331.1
Autoantibodies against tyrosyl-tRNA synthetase
and its separated domains at essential hypertension
M. Yu. Grom1, L. F. Yakovenko2, V. M. Granich3, A. S. Dobrohod3,
O. O. Torbas3, G. D. Radchenko3, Yu. M. Sirenko3, L. L. Sidorik2, A. I. Kornelyuk2
1 Educational and Scientifi c Center "Institute of Biology"
Taras Shevchenko National University of Kyiv
64/13, Volodymyrska Str., Kyiv, Ukraine, 01601
2 Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
3 National Scientifi c Center "M. D. Strazhesko Institute of Cardiology, NAMS of Ukraine"
5, Narodnogo Opolchennya Str., Kyiv, Ukraine, 03680
grom.m.yu@gmail.com
In addition to the key role in biosynthesis some aminoacyl-tRNA synthetases provide non-canonical functions.
Particularly, separated fragments of tyrosyl-tRNA synthetase (TyrRS) involved into angiogenesis and infl am-
mation. Meanwhile, the vascular infl ammation and endothelial dysfunction are central characteristics of the
pathogenesis of essential hypertension (EH). The latest studies highlight a role of antibodies in physiopathol-
ogy of EH. Aim. To investigate the full-length TyrRS and its domains as autoantigens in sera of the persons
with EH (n = 25), the healthy individuals with family history of the pathology (n = 12), and in the control group
of healthy subjects (n = 32). Methods. The recombinant TyrRS and its separated domains coupled with His-
tags and generated by Escherichia coli were purifi ed by chromatography on Ni-NTA-agarose. The levels of
specifi c autoantibodies (aAbs) in sera of volunteers were measured by ELISA and confi rmed in an immunob-
lotting assay. Results. Some subjects with elevated levels of aAbs against the full-length enzyme were de-
tected in the cohort studies. 52 % of the persons with EH as immunoreactive against miniTyrRS (p < < 0.001)
and 50 % against CTD (p = 0.002) were identifi ed. In 50 % of the healthy individuals with family history of
EH (p = 0.037) the levels of anti-CTD aAbs were elevated. Conclusions.The increased levels of aAbs against
miniTyrRS and CTD in sera of the persons with EH potentially may be used as a prognostic marker of the
disease severity or therapy effectiveness. Moreover, the immunoreactivity of healthy individuals with family
history of EH against CTD may be an early marker of hypertension.
K e y w o r d s: aminoacyl-tRNA synthetases, miniTyrRS, cytokine, endothelial dysfunction, cardiovas-
cular disease, prognostic marker.
© 2015 M. Yu. Grom et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Biopolymers and Cell.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited
Introduction
Tyrosyl-tRNA synthetase (TyrRS) is one of 20 con-
servative ancient enzymes that are critical at the initial
stage of protein synthesis. The aminoacylation reac-
tion, catalyzed by aminoacyl-tRNA synthetases, at-
taches each amino acid to its cognate tRNA [1, 2]. In
addition to the aminoacylation, tRNA synthetases per-
form other non-canonical functions due to the interac-
tions with various cellular partners [3]. New missions
can be associated with their cytoplasmic forms as well
as with nuclear and secreted extracellular forms that af-
fect the signaling, immune response, and pathways of
the cardiovascular development [4, 5]. Considering the
functional versatility of ARSs, their expanded functions
and expression may be associated with the pathology
of various human diseases [6]. These enzymes are im-
plicated into the neuronal diseases [7–9], tumorogene-
256
M. Yu. Grom, L. F. Yakovenko, V. M. Granich et al.
sis, [10], autoimmune diseases, namely, antisyn-
thetases syndrom [11–13], and heart failure [14].
The native mammalian TyrRS is a procytokine
[15]. Under apoptotic conditions, it can be secreted
and split by leukocyte elastase into two fragments with
distinct cytokine properties [16, 17]. The N-ter minal
catalytic fragment (miniTyrRS) with a Glu-Leu-Arg
(ELR) cytokine motif is a potent promoter of the an-
giogenesis [18] and polymorphonuclear leu kocytes
recruitment [19, 20]. The C-terminal domain (CTD)
has a high sequence similarity to the mature form of
the pro-infl ammatory cytokine-like protein known
as hu man Endothelial-Monocyte-Activating Poly-
pep ti de (EMAP II) [21] endowed with angiogenic
properties [22, 23].
Considering that the functional diversity of ARSs is
often associated with pathological conditions, and that
the separated domains of TyrRS are actively involved
in the angiogenesis, we inferred a role of TyrRS in the
cardiovascular diseases. Moreover, taking into account
the capacity of the enzyme fragments to endothelio-
cytes recruitment [24–27], probably TyrRS is patho-
logically associated with essential hypertension (EH).
The latest studies are focused on the activities of
TyrRS domains in the treatment of cardiovascular dis-
eases (CVD) [28–30], but they do not consider the im-
portance of specifi c autoantibodies (aAbs) against
TyrRS and its natural fragments. Meanwhile, the role
of antibodies in the pathogenesis of CVD, including
EH, is highlighted [31]. Therefore, the investigation of
aAbs against TyrRS and its natural fragments can im-
prove our understanding of an importance of the en-
zyme and its separated domains in health and patholo-
gies in general, EH in particular. The purpose of this
study was to identify the autoantibodies against TyrRS
and its individual modules in sera of the persons with
EH, the healthy individuals with family history of EH,
and the normal healthy subjects in a control group.
Materials and Methods
Patients and Sera
128 persons with EH were examined (35.3 % fema-
les and 64.7 % males; mean ± SD ages 48.4 ± 27,6).
All of them had high blood pressure from 7 to 20 years.
Serum samples were selected from 25 well-charac-
terized persons with EH and with or without target or-
gan damage, 12 healthy individuals with fa mily history
of EH, and 32 healthy volunteers. The males were re-
cruited into all of the cohort studies in a higher propor-
tion. This research was conducted in compliance with
the declaration of Helsinki and was approved by the
local ethics committee in the National Scientifi c Center
«M.D. Strazhesko Institute of Car diology» of NAMS
of Ukraine. All subjects were informed of the study
purposes, and their informed consents were obtained.
Production and purifi cation
of TyrRS and its separated domains
Generation of the recombinant full-length His-TyrRS
(528 aa), His-miniTyrRS (362 aa), and His-CTD (166
aa) of Bos taurus has been performed according to our
previous report [14]. The use of the bovine proteins is
valid because of a high identity to the human TyrRS
and its natural fragments (≈95 %). The constructed
plasmid vectors designated as pET-30a-TyrRS, pET-
30a-miniTyrRS, and pET-30a-His-CTD were trans-
formed into E. coli BL21 (DE3) pLysE cells (Novagen,
Madison, WI) grown in Lysogeny broth (LB) at 37 C
to optical density (OD) of 0.7–0.9 (600 nm). The ex-
pression of recombinant proteins with 1 mM iso pro-
pyl-β-D(2)-thioga lacto pyra noside (IPTG, Fermentas,
Cam bridge, United Kin gdom) was induced for 4 h.
Affi nity purifi cation of the recombinant proteins from
the cultural media using nickelnitriloacetic acid (Ni-
NTA resin, Thermo Scientifi c, USA) was carried out
according to the manufacturer’s recommendations.
The purity of His-TyrRS, His-mini-TyrRS, and His-
CTD was confi r med by sodium dodecyl sulfate-poly-
acrylamide gel electrophoresis (SDS-PAGE) using a
mixture of mar ker proteins (Fermentas, Lithuania).
ELISA assay
Specifi c binding of serum IgG aAbs to the recombi-
nant enzyme or its separated domains was analy zed
using direct solidphase ELISA. TyrRS, miniTyrRS,
or CTD (1 μg/well) in a phosphate-buffered saline
(PBS, pH 7.4) were incubated in 96-well polysty-
rene plates. Then the plates were washed ten ti mes
with PBS containing 0.1 % Tween-20 (PBS-T), and,
in order to block non-specifi c binding, the samples
257
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension
were incubated for 1 h at 37 C with 100 μl of PBS-T
added to each well. Subsequently, the wells loaded
with 1 : 50 diluted aliquots of sera were incubated
for 18 h at 4 C after washing with PBS-T. 100 μl of
horseradish peroxidase (HRP)-conjugated goat anti-
human IgG antibodies (Sigma, USA) were added to
each well and incubated for 1 h at 37 C. The plates
were washed again with PBS-T, then with the sub-
strate solution, containing 0.02 % H2O2, 0.1 M cit-
rate-phosphate buffer (pH 5.8), and 0.5 mg/mL 2,2’-
azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)
sodium salt (Sigma, USA), was added to each well.
After 20 min of incubation at 37 C, the absorbance
was measured at 405 nm in ELISA reader. PBS, pre-
immune serum of rabbit, and secondary antibodies
served as negative controls. The sera from immu-
nized by the full-length TyrRS rabbits were used as
positive controls. For each sample, the OD of the un-
coated well was subtracted from the OD of the coat-
ed well and then subjected to the data analysis. The
OD values greater than the mean + 2 SD values of
the normal controls were considered as positive.
Western blot analysis of recombinant peptides
The bacterially expressed His-TyrRS, His-miniTyrRS,
and His-CTD recombinant proteins were boiled, re-
solved by 12 % SDS-PAGE, and electrotransferred
to the nitrocellulose membrane (Amersham Bios ci-
ence, Germany). The membrane was divided into strips
and blocked by 5 % non-fat milk in PBS-T for 1 h at
room temperature followed by a triple wash with PBS
containing 0.1 % Tween-20. The strips with PBS-T,
immunized by TyrRS rabbit serum (1 : 75), and sera
of the control healthy individuals, or the healthy sub-
jects with family history of CVD, or the patients
with EH (1:100) were incubated for 18 h at 4 C. The
peroxidase-conjugated secondary antibodies (Sigma,
USA) to the strips after washing and incubated were
added for 1 h at a room temperature. The strips were
washed, and the immunoreactivity was detected by
ChemiDoc System (Bio-Rad Laboratories, USA).
Statistical analysis
All statistical analyses were performed using the Sta-
tistica software, version 7.0. Differences in non-par-
ametric data were tested by the Mann–Whitney test.
A P-value less than 0.05 was considered as statisti-
cally signifi cant.
Results
Production and characterization
of recombinant TyrRS, miniTyrRS, and CTD
To generate the recombinant full-length TyrRS, mi ni-
TyrRS, and CTD, we expressed them in the E. coli
BL21 (DE3) pLysE cells using the pET-30a expression
system and His-tag sequence in order to facilitate the
purifi cation of the recombinant proteins. After induc-
tion with IPTG we observed high levels of the His-
TyrRS, His-miniTyrRS, and His-CTD expression in
bacterial cells. Then recombinant proteins were puri-
fi ed on Ni-NTA agarose under denaturing conditions.
The required purity (more than 95 %) of the proteins
was confi rmed by SDS-PAGE (data not shown).
Detection of anti-TyrRS aAbs,
anti-mini-TyrRS, and anti-CTD by ELISA
The presence of anti-CTD, anti-mini-TyrRS, and anti-
TyrRS aAbs in the serum samples of the persons with EH,
Fig. 1. Anti-TyrRS aAb levels in sera from persons with EH,
he althy individuals with family history of EH and healthy con-
trols shown as OD values. The line shows the cut-off value and
means median +2SD values for the healthy controls
258
M. Yu. Grom, L. F. Yakovenko, V. M. Granich et al.
Fig. 2. Anti-mini-TyrRS (A, C, E) and anti-CTD (B, D, F) aAb levels in sera from persons with EH, healthy individuals wit family
history of EH and healthy controls shown as OD values. The lines (A, B) show the cut-off values and mean median +2SD values for
the healthy controls. Data (D–F) are presented as box plots, where the boxes represent the 25th to 75th percentiles, the points within
the boxes represent the median, and the lines outside the boxes represent the minimum and maximum values. Differences were ana-
lyzed by the Mann–Whitney U-test
259
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension
the healthy individuals with family history of EH, and the
normal controls was assessed by ELISA. The serum sam-
ples with OD values greater than the mean +2SD values
of the controls were considered as positive.
Anti-TyrRS (6.2 %), anti-miniTyrRS (15.6 %), and
anti-CTD (24 %) aAbs were detected in serum sam-
ples of the healthy volunteers (data not shown).
Anti-TyrRS positive sera in 12 % (3 of 25) of the
persons with EH were observed (Fig. 1). The elevat-
ed levels of anti-miniTyrRS antidobies were detected
in 52 % (13 of 25) of the persons with EH (Fig. 2, A).
Anti-CTD positive sera were shown in 60 % (15 of
25) of the persons with EH and 50 % (6 of 12) of the
individuals with family history of EH (Fig. 2, B).
The serum anti-miniTyrRS concentrations were sig-
nifi cantly higher in the persons with EH compared
with those in the Ab-negative normal healthy volun-
teers (p < 0.001). The serum levels of anti-CTD aAbs
were elevated not only among the persons with EH
(p = 0.002), but also among the healthy individuals
with family history of the pathology (p = 0.037).
Detection of anti-TyrRS, anti-mini-TyrRS,
and anti-CTD aAbs by Western blotting
The ELISA representative serum samples (positive,
poorly and moderate reactive) of each group were
subsequently confi rmed by Western blotting against
the full-length TyrRS (Fig. 3, A) and its natural frag-
ments (Fig. 3, B).
Discussion and Conclusion
A lot of studies postulate a role of autoantibodies in
the pathogenesis of hypertension [32]. For several
decades it was known that EH is associated with the
elevated serum levels of IgG and IgM autoantibodies
[33, 34]. They can be involved into pathogenic reac-
tions by binding to antigens expressed on the surface
of endogenous cells, that leads to the destruction of
cells via complement- or leukocyte-dependent inter-
actions (type II hypersensitivity reaction) [35]. aAbs
may form «immune complexes», that can be deposit-
ed in various tissues and cause the local infl ammatory
responses (type III hypersensitivity) [36]. They also
can act as non-immunogenic agonists to the receptors
(so-called «type V hypersensitivity»).
The numerous studies demonstrate the importance
of autoantibodies against theangiotensin II type-1 re-
ceptors, [37, 38], alpha-1 adrenergic receptors [39],
beta-1 adrenergic receptors [40], L-type voltage gated
Fig. 3. Immunoreactivity of healthy subjects, individuals with
family history of EH, and persons with EH against TyrRS (40 μg
for each protein) (A), miniTyrRS (B), and CTD (C), obtained by
Western blotting. Lines 1–3 represent the high, moderate, and
low reactive sera of healthy volunteers against relevant protein
according to ELISA; lines 4–6, by analogy, for individuals with
family history of EH; lines 7–9 for persons with hypertension. C
is control line, incubated with serum of rabbit immunized by
full-length TyrRS; M is protein MW marker
260
M. Yu. Grom, L. F. Yakovenko, V. M. Granich et al.
calcium channels [41], and heat shock proteins 70 and
60 [42–44] in the hypertension pathogenesis. The role
of TyrRS and its natural fragments as well as autoanti-
bodies against them in EH remains unknown.
EH is a multifactorial disease with indefi nite etiol-
ogy, its pathogenesis is clearly associated with the
development of vascular endothelial dysfunction, cha-
racterized by pro-trombotic, pro-infl ammatory and
pro-constrictive vessel status [45]. Meanwhile, the
endotheliocytes recruitment and the pro-infl amma-
tory effects are the key properties of both distinct
domains of TyrRS. [5, 17]. Considering all these facts,
the involvement of natural fragments of the enzyme
into pathogenesis of EH is quite possible.
This is the fi rst investigation of the serum immu-
noreactivity of the persons with EH, the healthy in-
dividuals with family history of EH, and the healthy
subjects against TyrRS and its separated domains.
The study demonstrates the presence of persons with
elevated levels of autoantibodies against the full-
length enzyme, miniTyrRS, and CTD in the normal
healthy cohort. Such kind of immunoreactivity can
be stipulated by some undetected infl ammatory proc-
ess that resulted in the secretion of TyrRS or the ap-
pearance of the full-length protein in the intercellular
space due to apoptosis. Our data demonstrate the sig-
nifi cant immunoreactivity against mini-TyrRS (52 %)
and CTD (60 %) among the persons with EH. Surp-
risingly, we found out the increased levels of autoan-
tibodies against CTD in sera of 50 % of the healthy
individuals with family history of the pathology.
Difference in the values of aAbs against the full-
length enzyme and its natural fragments can be ex-
plained by the potential existence of the epitopes
which are responsible for the cytokine activities and
are sequestered in a native form by each other. The
regions of cytokine activity – ELR on miniTyrRS
and heptapeptide (Arg13-Thr19) on the N-terminus
of CTD – in the full-length TyrRS have «face-to-
face» orientation, conditioned by the electrostatic in-
teractions [46]. Under the apoptotic conditions, spe-
cifi cally infl ammation, the native enzyme is secreted
into intercellular space and can be cleaved by a ex-
tracellular protease such as leukocyte elastase. Mo-
reover, the regions of cytokine activity can be un-
masked in a cell via tRNA connection [46]. As a re-
sult, both sequences providing the cytokine activity,
become available and two distinct fragments obtain
new cytokine functions [16]. It seems absolutely
logically to assume normally hidden sequences to be
extremely immunogenic. The immunoreactivity of the
persons with EH as well as of the individuals with
family history of pathology suggests the presence of
natural fragments of TyrRS, the formation of which
is possible in terms of infl ammation [17], known to
be a component of the EH pathogenesis.
Earlier we have demonstrated the TyrRS and its sep-
arated domains as autoantigens in heart failure caused
by the dilated cardiomyopathy, myocarditis and ischem-
ic heart disease [14]. The highest immunoreactivity for
the full-length enzyme and the lowest for CTD were
revealed. According to our recent fi ndings in sera of the
patients with hypertension the highest levels of aAbs
were found against the CTD and the lowest against the
full-length enzyme. The data comparison suggests po-
tential involvement of aAbs against CTD and mini-
TyrRS into the EH pathogenesis.
A practical signifi cance of TyrRS and its separated
domains is a «double-edged weapon». On the one
hand, TyrRS is one of eight aminoacyl-tRNA syn-
thetases involved into the antisynthetase syndrome
[12], its mutant form occurs in Charcot-Marie-Tooth
hereditary neuropathy [47]. On the other hand, mini-
TyrRs is a potential drug in the myocardial ischemia
treatment [30]. Its particular role also was demon-
strated in the platelet recovery in the patients suffer-
ing from the life-threatening thrombocytopenia or
the bone marrow failure [28]. For recovery of cardi-
ac function after myocardial infarction [29] CTD
can be applied as an antiangiogenic stimulus [27].
However, the infl uence of aAbs on TyrRS and its
separated domains in the disease pathogenesis as
well as in the treatment strategies remains to be elu-
cidated. Potentially, the elevated levels of autoanti-
bodies against mini-TyrRS and CTD in sera of the
persons with EH may be used as prognostic markers
of the EH severity or the therapy effectiveness.
Moreover, the immunoreactivity of healthy individ-
uals with family history of EH against CTD may be
an early marker of hypertension.
261
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension
Declaration of Interest
The authors report no confl icts of interest. The authors
alone are responsible for the content and writing of
the paper.
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Аутоантитіла проти тирозил-тРНК синтетази
та її окремих доменів при гіпертонічній хворобі
М. Ю. Гром, Л. Ф. Яковенко, В. М. Гранiч,
Г. С. Доброход, О. О. Торбас, Г. Д. Радченко,
Ю. М. Сиренко, Л. Л. Сидорик, О. І. Корнелюк
Окрім ключової ролі у біосинтезі білка певні аміноацил-
тРНК синтетази виконують також неканонічні функції.
Зокрема окремі домени тирозил-тРНК синтетази залучені
до ангіогенезу та запальних реакцій. Тим часом, судинні за-
палення і дисфункція ендотелію є центральними характе-
ристиками патогенезу гіпертонічної хвороби (ГБ). Останні
дослідження підкреслюють роль антитіл в патофізіології
ГБ. Мета. Дослідити повнорозмірну TyrRS і її окремі доме-
ни як аутоантигени в сироватках осіб з ГБ (n = 25), у здоро-
вих осіб з сімейною історією патології (n = 12), і в контр-
ольній групі здорових осіб (n = 32). Методи. Ре ком бінантна
TyrRS і її окремі домени, пов'язані з His-теґами, експресува-
лися в клітинах E.coli, та очищалися хроматографією на Ni-
NTA-агарозе. Рівні специфічних аутоантитіл (aAbs) в сиро-
ватці добровольців були виміряні методом ІФА та підтвер-
джені в імуноблотингу. Результати.Некоторие пацієнти з
підвищеним рівнем aAbs проти повнорозмірного ферменту
були виявлені в когортних дослідженнях. 52 % осіб з ГБ
були ідентифіковані як імунореактивні проти mi niTyrRS (р
< 0,001) і 50 % проти CTD (р = 0,002). У 50 % здорових осіб
263
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension
з сімейною історією ГБ (р = 0,037) рівні анти-CTD aAbs бу-
ли підвищені. Висновки. Збільшення рівнів aAbs проти mi-
niTyrRS і CTD у сироватці осіб з ГБ потенційно може бути
використане як прогностичний маркер ступеня тяжкості за-
хворювання та ефективності терапії. Крім того, імунореак-
тивність проти CTD здорових людей з сімейною історією
ГБ може бути раннім маркером гіпертонії.
Ключов і слова: аміноацил-тРНК синтетази, mini-TyrRS,
цитокін, ендотеліальна дисфункція, серцевосудинні захво-
рювання, прогностичний маркер.
Аутоантитела против тирозил-тРНК синтетазы
и ее отдельных доменов при гипертонической болезни
М. Ю. Гром, Л. Ф. Яковенко, В. Н. Гранич,
А. С. Доброход, Е. А. Торбас, А. Д. Радченко,
Ю. М. Сиренко, Л. Л. Сидорик, А. И. Корнелюк
Кроме ключевой роли в процессе биосинтеза белка ряд аминоа-
цил-тРНК синтетаз также исполняют, так называемые, некано-
нические функции. В частности, отдельные домены тирозил-
тРНК синтетазы вовлечены в ангиогенез и воспалительные ре-
акции. Между тем, сосудистой воспаление и дисфункция
эндотелия яв ля ются центральными характеристиками пато-
генеза гипер тонической болезни (ГБ). Последние исследо-
вания подчеркивают роль антител в патофизиологии ГБ.
Цель. Исследовать полноразмерную TyrRS и ее отдельные
домены как аутоантигены в сыворотках лиц с ГБ (n = 25), у
здоровых лиц с семейной историей патологии (n = 12), и в
контрольной группе здоровых лиц (n = 32). Методы. Реком-
бинантная TyrRS и ее отдельные домены, связанные с His-
тегами и экспрессированные в E. coli, очищали хроматогра-
фией на Ni-NTA-агарозе. Уровни специфических аутоанти-
тел (aAbs) в сыворотке добровольцев были измерены мето-
дом ИФА и подтверждены в иммуноблоттинге. Результаты.
Некоторые пациенты с повышенным уровнем aAbs против
полноразмерного фермента были обнаружены в когортных
исследованиях. 52 % лиц с ГБ были идентифицированы как
иммунореактивные против miniTyrRS (р < 0,001) и 50 % про-
тив CTD (р = 0,002). У 50 % здоровых лиц с семейной исто-
рией ГБ (р = 0,037) уровни анти-CTD aAbs были повышены.
Выводы. Увеличение уровней aAbs против miniTyrRS и CTD
в сыворотке у лиц с ГБ потенциально может быть использо-
вано в качестве прогностического маркера степени тяжести
заболевания и эффективности терапии. Кроме того, иммуно-
реактивность против CTD здоровых людей с семейной исто-
рией ГБ может быть ранним маркером гипертонии.
Ключевые слова: аминоацил-тРНК синтетазы, mini-Tyr
RS, цитокин, дисфункция эндотелия, сердечнососудистые
заболевания, прогностический маркер
Received 20.05.15
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