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КАРДИОРЕСПИРАТОРНЫХ
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| JOURNAL OF CARDIORESPIRATORY RESEARCH
№
1 | 2020
23
UDC: 616.12-009.72: 612.017.1
Alyavi Anis Lutfullaevich,
Doctor of Medical Sciences, Professor,
Academician of the Academy of Sciences of Uzbekistan,
Grant Manager of the Republican Specialized Scientific and
Practical Medical Center for Therapy and Medical Rehabilitation
of the Ministry of Health of Uzbekistan, Tashkent, Uzbekistan.
Tulyaganova D.K.
PhD, senior researcher of the Republican Specialized
Scientific and Practical Medical Center for
Therapy and Medical Rehabilitation, Ministry of Health
of Uzbekistan, Tashkent, Uzbekistan
Nuritdinova S.K.
PhD, senior researcher of the Republican Specialized
Scientific and Practical Medical Center for Therapy and
Medical Rehabilitation, Ministry of Health
of Uzbekistan, Tashkent, Uzbekistan
Khan T.A.
junior research assistant of the Republican Specialized
Scientific and Practical Medical Center for Therapy
and Medical Rehabilitation, Ministry of Health
of Uzbekistan, Tashkent, Uzbekistan
Nazarova G.A.
junior research assistant of the Republican Specialized
Scientific and Practical Medical Center for Therapy
and Medical Rehabilitation, Ministry of Health
of Uzbekistan, Tashkent, Uzbekistan
Saidov Sh.B.
junior research assistant of the Republican Specialized
Scientific and Practical Medical Center for Therapy
and Medical Rehabilitation, Ministry of Health
of Uzbekistan, Tashkent, Uzbekistan
CHANGES IN THE CYTOKINE STATUS WITH STABLE ANGINA (REVIEW)
For citation:
Alyavi A.L., Tulyaganova D.K., Nuritdinova S.K., Khan T.A., Nazarova G.A., Saidov Sh.B. Role of cytokines in
ischemic heart disease. Journal of cardiorespiratory research. 2020, vol. 1, issue 1, pp.23-29
http://dx.doi.org/10.26739/2181-0974-2020-1-2
ANNOTATION
This review summarizes the current evidence on the role of cytokines in the pathogenesis of ischemic myocardial damage. It described
the important role of inflammation in the development of coronary heart disease. The role of individual cytokines in the pathogenesis
of coronary artery disease and the most frequent forms of it - angina. It is shown that in patients with coronary heart disease progression
of the disease is due to an imbalance in cytokine system, elevated pro-inflammatory cytokines (TNF, IL-1
β
, IL-6). Anti-inflammatory
cytokines (IL-4, IL-10) inhibit the secretion of proinflammatory cytokines by limiting excessive intensity of the immune response.
Revealed increasing levels of TGF-
β
1 as a key cytokine that promotes the development of fibrosis in the wall of the heart and blood
vessels. The interrelation between improving markers of inflammation and the development of coronary heart disease, the predictive
value of these markers of inflammation in patients with stable coronary heart disease: angina of effort of different functional classes.
Key words:
ischemic heart disease, stable angina, cytokines.
Аляви
Анис
Лютфуллаевич
доктор
медицинских
наук
,
профессор
,
академик
АН
РУз
,
руководитель
гранта
Республиканского
специализированного
научно
-
практического
медицинского
центра
терапии
и
медицинской
реабилитации
МЗ
РУз
.
г
.
Ташкент
,
Узбекистан
ЖУРНАЛ
КАРДИОРЕСПИРАТОРНЫХ
ИССЛЕДОВАНИЙ
| JOURNAL OF CARDIORESPIRATORY RESEARCH
№
1 | 2020
24
Туляганова
Д
.
К
.
к
.
м
.
н
,
с
.
н
.
с
.
Республиканского
специализированного
научно
-
практического
медицинского
центра
терапии
и
медицинской
реабилитации
МЗ
РУз
.
г
.
Ташкент
,
Узбекистан
Нуритдинова
С
.
К
.
к
.
м
.
н
.,
с
.
н
.
с
.
Республиканского
специализированного
научно
-
практического
медицинского
центра
терапии
и
медицинской
реабилитации
МЗ
РУз
.
г
.
Ташкент
,
Узбекистан
Хан
Т
.
А
.
м
.
н
.
с
.
Республиканского
специализированного
научно
-
практического
медицинского
центра
терапии
и
медицинской
реабилитации
МЗ
РУз
.
г
.
Ташкент
,
Узбекистан
Назарова
Г
.
А
.
м
.
н
.
с
.
Республиканского
специализированного
научно
-
практического
медицинского
центра
терапии
и
медицинской
реабилитации
МЗ
РУз
.
г
.
Ташкент
,
Узбекистан
Саидов
Ш
.
Б
.
м
.
н
.
с
.
Республиканского
специализированного
научно
-
практического
медицинского
центра
терапии
и
медицинской
реабилитации
МЗ
РУз
.
г
.
Ташкент
,
Узбекистан
РОЛЬ
ЦИТОКИНОВ
ПРИ
ИШЕМИЧЕСКОЙ
БОЛЕЗНИ
СЕРДЦА
(
ОБЗОР
)
АННОТАЦИЯ
В
обзоре
обобщены
современные
данные
,
касающиеся
роли
цитокинов
в
патогенезе
ишемических
поражений
миокарда
.
Описана
важная
роль
воспаления
в
развитии
ишемической
болезни
сердца
.
Определена
роль
отдельных
цитокинов
в
патогенезе
ИБС
и
самой
часто
встречающейся
ее
формы
-
стенокардии
.
Показано
,
что
у
больных
ишемической
болезнью
сердца
прогрессирование
заболевания
связано
с
дисбалансом
в
цитокиновой
системе
,
повышением
содержания
провоспалительных
цитокинов
(
ФНОα
,
ИЛ
-1
β
,
ИЛ
-6).
Противовоспалительные
цитокины
(
ИЛ
-4,
ИЛ
-10)
угнетают
секрецию
провоспалительных
цитокинов
,
ограничивая
чрезмерную
интенсивность
иммунного
ответа
.
Выявлено
повышение
уровня
ТФР
-
β
1
как
ключевого
цитокина
,
способствующего
развитию
фиброза
в
стенке
сердца
и
сосудов
.
Обсуждается
взаимосвязь
повышения
уровня
маркеров
воспаления
и
развития
ишемической
болезни
сердца
,
прогностическая
ценность
этих
маркеров
воспаления
у
пациентов
,
страдающих
стабильными
формами
ишемической
болезни
сердца
:
стенокардией
напряжения
различных
функциональных
классов
.
Ключевые
слова
:
ишемическая
болезнь
сердца
,
стабильная
стенокардия
напряжения
,
цитокины
.
Alyavi Anis Lyutfullayevich
tibbiyot fanlari doktori, professor, O'zbekiston Respublikasi
Fanlar akademiyasi akademigi, O'zbekiston Respublikasi Sog'liqni
saqlash vazirligining Respublika ixtisoslashtirilgan terapiya
va tibbiy reabilitatsiya ilmiy-amaliy tibbiyot
markazining grant rahbari. Toshkent, O'zbekiston
Tulyaganova D. K.
O'zbekiston Respublikasi Sog'liqni saqlash vazirligining
Respublika ixtisoslashtirilgan terapiya va tibbiy reabilitatsiya
ilmiy-amaliy tibbiyot markazining katta ilmiy hodim. Toshkent, O'zbekiston
Nuritdinova S.K.
O'zbekiston Respublikasi Sog'liqni saqlash vazirligining
Respublika ixtisoslashtirilgan terapiya va tibbiy reabilitatsiya
ilmiy-amaliy tibbiyot markazining katta ilmiy hodim. Toshkent, O'zbekiston
Khan T.A.
O'zbekiston Respublikasi Sog'liqni saqlash vazirligining
Respublika ixtisoslashtirilgan terapiya va tibbiy reabilitatsiya
ilmiy-amaliy tibbiyot markazining kichik ilmiy hodim. Toshkent, O'zbekiston
Nazarova G.A.
O'zbekiston Respublikasi Sog'liqni saqlash vazirligining
Respublika ixtisoslashtirilgan terapiya va tibbiy reabilitatsiya
ilmiy-amaliy tibbiyot markazining kichik ilmiy hodim. Toshkent, O'zbekiston
Saidov Sh.B.
O'zbekiston Respublikasi Sog'liqni saqlash vazirligining
Respublika ixtisoslashtirilgan terapiya va tibbiy reabilitatsiya
ilmiy-amaliy tibbiyot markazining kichik ilmiy hodim. Toshkent, O'zbekiston
YURAK ISHEMIK KASALLIGIDA SITOKINLARNING ROLI
(ADABIYOTLAR TAHLILI)
ANNOTATSIYA
Ushbu maqolada miokardni ishemik jarohatlanishida sitokinlarni ahamiyati haqida eng yangi ma’lumotlar ko’rsatilgan. Yurak ishemik
kasalligining rivojlanishida yallig’lanishni o’rni to’liq yoritilgan. Yurak ishemik kasalligi ya’ni ko’p uchrovchi stenokardiya
patogenezida ayrim sitokinlarni o’rni aniqlandi. YIK bor bemorlarda kasallikni zo’rayishi sitokinlar disbalansi bilan bog’liqligi,
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ayniqsa yallig’lanishiga qarshi sitokinlar (FNO
α
, IL-1
β
, IL-6) miqdorini oshishi ko’rsatildi. Yallig’lanishga qarshi sitokinlar (IL-4, IL-
10) yallig’lanish sitokinlar ishlab chiqarish sitokinlari kamaytiradi. TFR-
β
1 sitokini miqdorini oshishi yurak va qon tomir devorida
fibrozni rivojlanishidan dalolat beradi. Yallig’lanish markerlari miqdorini oshishi yurak ishemik kasalliga rivojlanishida bog’liqlik
borligini, va yurak ishemik kasalligining barcha shakllari bilan kasallangan bemorlar uchun muhim ahamiyatga egaligi muhokama
qilinmoqda.
Kalit so’zi:
yurak ishemik kasalligi, stabil zo’riqish stenokardiyasi, sitokinlar
Cardiovascular disease (CVD) remains the main cause
of morbidity and mortality in the world [1]. Coronary heart
disease (CHD) gets the most significant part in the structure of
cardiovascular diseases, which maintains one of the leading
places among the causes of mortality among the adult population
[2]. According to estimates by the World Health Organization
(WHO), more than 17 million people die from CVD every year
in the world, including more than 7 million from CHD [3].
Reports of the State Research Center for Preventive Medicine in
2013, the mortality rate of the population at an economically
powerful age (15-72 years) in the Russian Federation from IHD
amounted to 181.36 per 100 thousand people aged 15–72 years,
among men - 269.23 and 103.01 - among women [4]. In Russia,
coronary heart disease is the most common reason for referring to
medical institutions for all CVDs and accounts for 28% of cases.
Stable angina pectoris is the most prevalent form of chronic
coronary heart disease [5,6]. According to the State Research
Center for Preventive Medicine, in Russia 10 million able-bodied
people suffer from coronary heart disease, more than a third of
them in the form of stable angina pectoris. The annual mortality
of patients with stable angina is 2%.
The role of inflammation in the pathogenesis of
atherosclerosis of coronary arteries and coronary artery disease
Many data show that systemic inflammation is frequent
CVD and implicate that inflammation contributes to damage and
dysfunction of the cardiovascular system. In the pathogenesis of
atherosclerosis and exacerbation of coronary heart disease, the
role of the main link is assigned to the inflammatory reaction. The
inflammatory process develops at the local level, which is
determined by the basic mechanisms of inflammation, and the
systemic is the systemic inflammatory response syndrome
(SIRS). Atherosclerosis of the coronary arteries is the
pathomorphological basis of IHD. With atherosclerosis, signs of
a local and systemic non-specific inflammatory process are
observed already in the early stages of damage to the blood vessel
wall. Atherosclerosis is known to be a chronic inflammatory
process, and even in the early stages of atherogenesis -
intracellular and extracellular deposition of lipids and formation
of lipid spots, inflammatory cells (macrophages and T-
lymphocytes) are already present [6,7]. These cells produce a
large number of cytokines, chemokines, and matrix
metalloproteinases, which cause the development of
atherosclerotic foci [8,9].
In atherosclerosis, there is an increase in the expression
of VCAM-1 adhesion molecules on endotheliocytes, which,
under the influence of pro-inflammatory chemoattractants, leads
to the migration of monocytes to intima of the arteries and their
subsequent transformation into foam cells. T-lymphocytes also
migrate, secreting cytokines that enhance local inflammation.
After plaque formation, the constant interaction of lymphocytes
and macrophages supports the inflammatory process [10].
Cytokines are known to have multidirectional regulatory effects
on the atherosclerotic process. So, proinflammatory cytokines
(TNF
α
, IL-1
β
, IL-6, IL-8) are considered atherogenic, and anti-
inflammatory cytokines (IL-4 and IL-10) as anti-atherogenic
mediators [11]. In patients with coronary artery disease,
inflammation is a nonlocal process limited to the zone of
atherosclerotic lesion of the vascular wall, inflammatory
reactions are systemic, accompanied by an increase in blood
levels of markers and mediators of inflammation [12].
Systemic Inflammatory Response Syndrome (SIRS) is
usually identified with systemic inflammation (SI). Systemic
inflammation is a typical, multisyndromic, phase-specific
pathological process that develops at the div and is
characterized by total inflammatory activity of endotheliocytes,
plasma factors, blood cells and connective tissue, as well as
microcirculatory disorders in vital organs and tissues with the
development of multiple organ failure [13]. CBO is represented
by several clinical and immunological phenomena: systemic
inflammatory response (SIRS), compensatory anti-inflammatory
syndrome (CARS) and mixed antagonistic response syndrome
(MARS). It was shown in experiments that, following an increase
in the production of cytokines characteristic of SIRS (TNF
α
, IL-
1
β
), inflammatory mediators characteristic of CARS (TGF
β
, IL-
4, IL-10) are produced and are antagonists of the first phase. Both
responses ultimately form MARS, which is characterized by the
simultaneous production of pro- and anti-inflammatory cytokines
[14].
Systemic Inflammatory Response Syndrome (SIRS) is
usually identified with systemic inflammation (SV). Systemic
inflammation is a typical, multiple syndrome, a phase-specific
pathological process that develops at the div level and is
characterized by the total inflammatory activity of
endotheliocytes, plasma factors, blood cells, and connective
tissue, as well as microcirculatory disorders in vital organs and
tissues with the development of multiple organ failure [13]. SIRS
is represented by several clinical and immunological phenomena:
systemic inflammatory response (SIRS), compensatory anti-
inflammatory syndrome (CARS), and mixed antagonistic
response syndrome (MARS). It was shown in experiments that,
following an increase in the production of cytokines characteristic
of SIRS (TNF
α
, IL-1
β
), inflammatory mediators characteristic of
CARS (TGF
β
, IL-4, IL-10) are produced and are antagonists of
the first phase. Both responses ultimately form MARS, which is
characterized by the simultaneous production of pro- and anti-
inflammatory cytokines [14].
The development of SIRS is accompanied by the
activation of the atherosclerotic process. According to modern
concepts, an important component of the pathogenesis of
coronary heart disease is a systemic inflammatory activity. SIRS
most often proceeds subclinically and is the main factor
underlying the formation of atherosclerotic plaque, its
destabilization, and subsequent rupture [15]. The severity of SIRS
is determined by the level of immunological biomarkers.
According to the results of numerous studies, inflammatory
markers associated with atherosclerosis are IL-6 [16], IL-8 [17],
IL-1-
β
, and TNF-
α
[18].
The cytokine status changes in patients with coronary artery
disease
Violation of the synthesis of cytokines or the expression
of receptors for them has a damaging effect on the myocardium.
Pro-inflammatory cytokines have a negative inotropic effect,
cause cardiac remodeling (irreversible cavity dilatation and
cardiomyocytes hypertrophy), impaired endothelium-dependent
dilatation of arterioles, and increased cardiomyocytes apoptosis.
The decrease in cardiac output that occurs after myocardial
damage stimulates the extramyocardial production of these
mediators. The components of humoral and cellular immunity are
involved in the development of immuno-inflammatory activation.
Besides, the function of the heart can change not only due to
damage to the cardiomyocytes, but also a change in the activity
of cardiofibroblasts. Cardiofibroblasts provide physiological
post-stress remodeling. The participation of pro-inflammatory
cytokines in the formation of chronic inflammation in coronary
artery disease is confirmed in the experiment [19]. Depending on
the effect on the inflammatory process, cytokines are divided into
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two groups - pro-inflammatory (IL-1, IL-6, IL-8, TNF
α
, IL-12)
and anti-inflammatory (IL-4, IL-10, TGF-
β
) [20]. Pro-
inflammatory cytokines are an important and well-studied class
of biologically active substances that have an immunoregulatory
and inflammatory effect. The main pro-inflammatory cytokines
include TNF
α
, IL-1, and IL-6, IL-8. Tumor necrosis factor
α
(TNF
α
) is a cytokine with pronounced inflammatory properties.
It plays a decisive role in the development of inflammation, is an
active participant in the immune response, and takes part in the
regulation of cell apoptosis [21]. TNF
α
is synthesized mainly in
monocytes and macrophages, as well as in mast cells, fibroblasts,
endothelial cells. It stimulates the expression of the production of
IL-1
β
, IL-6, IL-8. This cytokine affects the functional properties
of the endothelium, affects coagulation, disrupts lipid
metabolism, stimulating atherogenesis. TNF
α
is considered one
of the key factors that ensure the interaction of endothelium and
white blood cells. Bozkurt et al. Found that prolonged infusion of
TNF
α
leads not only to a decrease in myocardial contractility but
also to irreversible dilatation of the ventricles of rat hearts [22].
The cardiodepressive effect of TNF
α
is probably associated with
a change in calcium cell homeostasis [23], activation of
metalloproteinases that induce the destruction of the fibrillar
collagen matrix [24]. The researchers found that in patients with
coronary artery disease there is an increase in the level of TNF
α
associated with the severity of the course of angina pectoris [25].
IL-1
β
, one of the main pro-inflammatory cytokines, is produced
primarily by phagocytes, macrophages, as well as fibroblasts,
lymphocytes, and epithelial cells. IL-1
β
activates and regulates
inflammatory, immune processes, activates neutrophils, T- and
B-lymphocytes stimulates the synthesis of proteins of the acute
phase of inflammation, pro-inflammatory cytokines (TNF
α
),
adhesion molecules, prostaglandins. IL-1
β
increases chemotaxis,
vascular wall permeability, cytotoxic and bactericidal activity,
which has a pyrogenic effect. The synthesis of IL-1
β
is
suppressed by anti-inflammatory cytokines such as IL-4 and IL-
10. An increase in the content of IL-1
β
was noted in many
diseases, including IHD. Violation of coronary blood flow,
accompanied by myocardial ischemia, leads to an increase in the
content of IL-1
β
in the blood. The researchers found that the
severity of IL-1
β
expression depends on the severity of the course
of angina pectoris and is most significant in severe angina pectoris
IV FC [25]. IL-1
β
takes an active part in the development of
atherosclerosis and the formation of the clinical course of
coronary heart disease, due to its effect on the function of the
endothelium and the blood coagulation system, the ability to
induce the synthesis of pro-inflammatory cytokines and
expression of adhesive molecules, stimulate procoagulant activity
and affect lipid metabolism. IL-6 pro-inflammatory cytokine
plays an important role in systemic inflammation, is the main
activator of the synthesis of acute-phase proteins in the liver.
Using IL-6, endothelial cells, monocytes are also activated, and
procoagulant reactions occur. Some studies [26] show the
importance of IL-6 as a predictor of the development of clinical
manifestations of atherosclerotic vascular lesions in healthy
individuals without signs of disease. IL-6 is produced by
activated
monocytes
or
macrophages,
fibroblasts,
endotheliocytes. In inflammation, TNF-
α
, IL-1
β
, and IL-6 are
sequentially secreted. Then, IL-6 begins to inhibit the secretion of
TNF-
α
and IL-1
β
, activate the production of proteins of the acute
phase of inflammation by the liver and stimulate the
hypothalamic-pituitary-adrenal system, which contributes to the
regulation of the inflammatory process, and therefore IL-6 can
also be considered pro-inflammatory, and as an anti-
inflammatory cytokine. The main effect of IL-6 is associated with
its participation as a cofactor in the differentiation of B-
lymphocytes, their maturation, and conversion into plasma cells
that secrete immunoglobulins. Besides, IL-6 promotes the
expression of the IL-2 receptor on activated immunocytes and
also induces the production of IL-2 by T cells. This cytokine
stimulates the proliferation of T-lymphocytes and the reaction of
hematopoiesis. In the invitro study, an increase in the level of IL-
6 was accompanied by a decrease in the contractile function of
myocytes [27].
It has been shown that the ability of IL-6 to transfer
inflammation from the acute phase to the chronic with the
involvement of mononuclear cells. It was proved that a high level
of IL-6 is associated with an unfavorable prognosis and an
increased level of TNF-
α
– with an increase in mortality of
patients. IL-8, a pro-inflammatory cytokine, plays an important
role in the initiation and maintenance of inflammation, is
responsible for the induction of adhesive molecules involved in
the interaction of leukocytes and endothelium and subsequent
extravasation of leukocytes at the site of the inflammatory
reaction. Induces the production of IL-8 damage to the vascular
endothelium. The main producers of IL-8 are activated
monocytes/macrophages and endothelial cells. According to the
authors of clinical trials, IL-8 is the only pro-inflammatory
cytokine that is associated with cardiovascular events
independently of other cytokines. Since IL-8 stimulates directed
migration of neutrophils, these results indicate that neutrophil
activation may be associated with the occurrence of
cardiovascular events [28]. It is known that cytokines can
modulate the functions of the cardiovascular system. Adverse
effects of pro-inflammatory cytokines are negative inotropic
effects, remodeling of the heart, activation of apoptosis
cardiomyocytes, and peripheral muscles.
Anti-inflammatory
cytokines
Anti-inflammatory
cytokines (IL-4, IL-10) inhibit the secretion of pro-inflammatory
cytokines, inhibit macrophage activity, reduce the expression of
adhesion molecules and reduce cytotoxicity [29]. IL-4, an anti-
inflammatory cytokine, is produced by activated T-lymphocytes
of type 2 helpers, basophils, mast cells, eosinophils. IL-4 is a
stimulator of the humoral link of immunity and allergies, plays
the role of one of the main negative regulators of the development
of cellular immunity reactions, by directly suppressing the
immunological reactions caused by cytokines of type I helper T
lymphocytes (INF-
γ
, IL-2, TNF) [30]. Anti-inflammatory
cytokines, in particular IL-4, are involved in limiting the activity
of the inflammatory response, inhibiting the secretion of pro-
inflammatory cytokines and thus regulating the severity of tissue
damage. According to modern data, in patients with coronary
artery disease the highest level of IL-4 was determined in the
group of patients with angina pectoris in comparison with the
control. The highest content of this cytokine was observed in
patients with angina pectoris II-III FC against the background of
post-infarction cardiosclerosis in comparison with the group of
patients with angina pectoris II-III FC without it [31]. An increase
in the level of IL-4 in patients with coronary heart disease seems
to be compensatory in response to the activation of pro-
inflammatory cytokines and acts as a factor stabilizing the course
of the disease. A relationship was found between an increase in
the level of pro-inflammatory cytokines (IL-6, TNF
α
) and the
severity of coronary heart disease. As the angina FC increases,
the level of pro-inflammatory cytokines increases, and the
concentration of IL-4 and IL-10 decreases [25].
There is a certain balance between pro- and anti-
inflammatory cytokines, it determines the activity of
atherosclerotic plaque and affects the course of IHD. In a stable
level of angina pectoris II FC, physiological mechanisms of
regulating the balance between pro- and anti-inflammatory
cytokines are activated, which makes it possible to suppress
inflammation in the atheromatous plaque due to blockage of the
secretion of pro-inflammatory cytokines with increased
production of IL-4 and IL-10. In angina pectoris IV FC, the
regulatory mechanisms in the cytokine network are violated and
an imbalance develops overexpression of IL-1
β
, IL-6, and TNF-
α
, which can have a cardiodepressive effect [32], increase
myocardial ischemia and, thus, significantly change the clinical
course of the disease. IL-10, the main anti-inflammatory cytokine
and one of the most sensitive markers of inflammation in CVD,
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reduces the secretion of pro-inflammatory cytokines (IL-1, IL-6,
IL-8, IL-12, TNF
α
), limits the excessive immune response [33].
IL-10 can inhibit damage and thrombosis of an atherosclerotic
plaque because it inhibits the activity of macrophages, the main
triggers of hypercoagulation. IL-10 reflects the reserve capacity
of the div. According to reported reviews, the content of IL-10
in the blood of patients with CVD decreases [34]. Stable angina
pectoris IV is characterized by minimal concentrations of IL-4
and IL-10, and a maximally elevated level of pro-inflammatory
cytokines [25]. Clinical studies have shown that factor risks of
poor prognosis of CVD were decreased levels of anti-
inflammatory cytokines (IL-10) and increased content of pro-
inflammatory cytokines (IL-8) and acute-phase proteins. In
chronic SI, the level of IL-10 exceeding 5 pg/ml was detected in
a small part of patients, and the critical level for acute SI of IL-10
of more than 25 pg/ml was recorded only in two cases. Therefore,
other cytokines act as an inhibitory mechanism in the SIRS
structure, one of which may be TGF-
β
1 [35]. Transforming
growth factor-
β
1 (TGF-
β
1) and the process of fibrosis in the
cardiovascular system TGF-
β
, an anti-inflammatory cytokine,
regulates the process of fibrosis in the cardiovascular system [36].
TGF-
β
is involved in the regulation of cell growth, proliferation,
differentiation, apoptosis, extracellular matrix production,
inflammation, angiogenesis, and tissue healing through exposure
to various types of cells [37].
TGF-
β
exists in 5 isoforms, three of them are expressed in normal
mammalian tissues and are designated as TGF-
β
1, TGF-
β
2, and
TGF-
β
3. The most pronounced expression and significant role in
inflammation, remodeling, and fibrosis of blood vessels and
myocardium have TGF-
β
1. TGF-
β
is produced by inflammatory
cells like a cytokine. The sources of TGF-
β
are mainly monocytes
and macrophages, fibroblasts, endotheliocytes, neutrophils,
eosinophils, mast cells, smooth muscle cells [30]. For the same
physiological processes, the stimulating and inhibitory effects of
TGF-
β
1, and in some cases the absence of its influence, were
revealed. The effect of TGF-
β
on a cell depends on its type, stage
of differentiation, and the presence of other cytokines. There is
evidence that TGF-
β
has both pro-inflammatory and anti-
inflammatory functions [36]. TGF-
β
helps resolve inflammation
and repair tissue. TGF-
β
exhibits its anti-inflammatory properties
by inhibiting the synthesis of pro-inflammatory cytokines, such
as IL-1
α
,
β
, TNF-
α
[36]. A literature review shows that a local or
systemic excess of this growth factor is associated with
unresolved
inflammation
[38].
Long-term
chronic
hyperproduction of TGF-
β
1 leads to hyperplasia of smooth
muscle cells, the progression of remodeling of the cardiovascular
bed. A reduced level of TGF-
β
1 can lead to an increase in
systemic inflammation (for example, an increase in the level of
IL-6), arterial stiffness, and hypertension [39]. Domestic
scientists have shown that myocardial ischemia is accompanied
by a decrease in the level of anti-inflammatory cytokine TGF-
β
1
in blood serum [40]. The researchers found an increase in the
concentration of TGF-
β
1 in the blood serum of patients with
coronary artery disease compared with the control group. The
highest content of this cytokine was observed in patients with
angina pectoris II-III FC against the background of post-
infarction cardiosclerosis in comparison with the group of
patients with angina pectoris II-III FC without it. Therefore, an
increase in TGF-
β
1 in the blood serum of patients with coronary
heart disease can be considered as a compensatory reaction aimed
at decreasing the activity of proinflammatory cytokines TNF-
α
,
IL-8 [31]. TGF-
β
1 is involved in the remodeling of blood vessels
and myocardium, and also takes part in the process of
neoangiogenesis. The development of fibrosis is associated with
excessive formation of connective tissue as a result of increased
collagen production and impaired degradation of extracellular
matrix proteins. TGF-
β
1 increases the collagen content due to a
direct effect on myofibroblasts, contributing to the fibrosis
process. The process of heart remodeling is realized due to the
influence of many factors, including the death of cardiomyocytes
by necrosis, apoptosis, and violation of the structural and
functional state of the extracellular matrix against the background
of increased fibrosis processes. This cytokine mediates the many
effects of angiotensin II, promotes the development of fibrosis by
inhibiting the activity of matrix metalloproteinases (MMPs), and
the induction of the synthesis of tissue inhibitors of
metalloproteinases. An increase in the level of TGF-
β
1 as a key
pro-fibrotic cytokine leads to the development of fibrosis in the
walls of the heart and blood vessels. Severe fibrosis of the
myocardium and vascular walls prevents them from stretching
during blood supply. On the one hand, this complicates the blood
supply to the LV and leads to an increase in diastolic
insufficiency, but on the other hand, it can protect the remaining
muscle fibers of the myocardium from overstretching during the
diastole for some time, which allows them to function with
increased efficiency by the Starling law. Limiting the
extensibility of blood vessels, especially in arteries of the elastic
type, leads to an acceleration of the return of blood and an
additional burden on the heart.
Thus, in the pathogenesis of atherosclerosis of coronary
arteries, as the pathomorphological basis of coronary heart
disease (CHD), inflammatory reactions occupy a key position.
With atherosclerosis, the inflammatory process develops both at
the local, but at the systemic level, systemic inflammatory
response (SIRS). The systemic inflammatory process most often
proceeds subclinically and is the main factor underlying the
formation of atherosclerotic plaque, its destabilization, and
rupture. Signs of local and systemic non-specific inflammatory
processes are observed already in the early stages of damage to
the blood vessel wall. The severity of the inflammatory response
is determined by the level of immunological biomarkers. As the
angina FC increases, the level of pro-inflammatory (TNF
α
, IL-1,
IL-6, IL-8) cytokines increases, and the concentration of anti-
inflammatory (IL-4 and IL-10) cytokines decreases. With stable
angina pectoris of FC II, physiological mechanisms of regulating
the balance between pro- and anti-inflammatory cytokines are
activated, inflammation in the atheromatous plaque is suppressed
due to blockage of the secretion of pro-inflammatory cytokines
and increased production of IL-4 and IL-10. With angina pectoris
IV FC, the regulatory mechanisms in the cytokine network are
violated and an imbalance develops between pro- and anti-
inflammatory cytokines with overexpression of IL-1
β
, IL-6, and
TNF-
α
, which have a cardiodepressive effect, enhance
myocardial ischemia and, therefore, change the clinical course of
the disease. high angina pectoris is associated with increased
expression of pro-inflammatory cytokines, which confirms the
presence of persistent inflammation, which increases the risk of
thrombotic complications and acute coronary syndrome, as in
step stable angina. TGF-
β
exhibits its anti-inflammatory
properties by inhibiting the synthesis of pro-inflammatory
cytokines, such as IL-1
α
,
β
, TNF-
α
. An increase in the level of
TGF-
β
1 as a key pro-fibrotic cytokine leads to the development
of fibrosis in the walls of the heart and blood vessels. Anti-
inflammatory cytokines are involved in limiting the activity of the
inflammatory response, inhibit the secretion of pro-inflammatory
cytokines, and regulate the severity of tissue damage. A decrease
in plasma levels of anti-inflammatory cytokines and an increased
content of pro-inflammatory cytokines and acute-phase proteins
indicate a higher risk and poor prognosis of CVD [41]. The
number of markers of inflammation (pro- and anti-inflammatory
cytokines) is constantly increasing. The introduction of
measurements of their level in practice will improve the quality
of diagnosis, identify risk groups, and more accurately evaluate
treatment outcomes and prognosis.
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