Інформація призначена тільки для фахівців сфери охорони здоров'я, осіб,
які мають вищу або середню спеціальну медичну освіту.

Підтвердіть, що Ви є фахівцем у сфері охорони здоров'я.

Мобильная версия

Регистрация Забыли пароль?


Коморбідний ендокринологічний пацієнт

Международный эндокринологический журнал Том 19, №2, 2023

Вернуться к номеру

Зміни ендотеліальної функції та оксидантного статусу при інсулінорезистентності й ожирінні за умов йодного дефіциту

Зміни ендотеліальної функції та оксидантного статусу при інсулінорезистентності й ожирінні за умов йодного дефіциту

Авторы: T.V. Todoriv, N.M. Voronych-Semchenko, O.M. Didushko
Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine

Рубрики: Эндокринология

Разделы: Справочник специалиста

Версия для печати


Резюме

Актуальність. Актуальність теми зумовлена значною поширеністю серцево-судинних захворювань та підвищенням витрат на медичне обслуговування, високим ризиком інвалідності, що характеризує медико-соціальну складову проблеми. Патологічні зміни можуть бути не тільки проявом кардіоваскулярної системи, а й розвиватися внаслідок інших захворювань, зокрема цукрового діабету, ожиріння та тиреоїдної патології. Одним із головних механізмів інвалідизації та смертності є макросудинні ускладнення, що можуть виникати за умов ендотеліальної дисфункції та оксидативного стресу. Мета дослідження: вивчити особливості змін показників ендотеліальної системи та оксидантного статусу у тварин із інсулінорезистентністю й ожирінням при належному забезпеченні йодом та йодному дефіциті. Матеріали та ­методи. Дослідження проведені на 75 статевозpілих щурах, які отримували високовуглеводну, високожирову дієти за умов належного та обмеженого забезпечення йодом, із подальшим аналізом маркерів вуглеводного обміну, тиреоїдного статусу, показників ендотеліальної функції, перекисного окиснення ліпідів й антиоксидантного захисту. Результати. Розвиток інсулінорезистентності та ожиріння при навантаженні дієти фруктозою та жирами супроводжується розвитком ендотеліальної дисфункції: у сироватці крові збільшується рівень ендотеліну-1 та активується індуцибельна NO-синтаза (iNO-синтаза), у міокарді зростає активність iNO-синтази порівняно з даними тварин, у яких харчовий раціон стандартний. Розвиток оксидативного стресу в дослідних тварин характеризує зростання вмісту дієнових кон’югат і реактивних сполук тіобарбітурової кислоти в сироватці крові та міокарді на тлі пригнічення антиоксидантних ферментів сироватки крові (каталаза, супероксиддисмутаза, церулоплазмін, глутатіонпероксидаза, глутатіонредуктаза). Ступінь ендотеліальної дисфункції та інтенсивність ліпопероксидації зростають при гіпотиреоїдній дисфункції на тлі йодного дефіциту. Висновки. Метаболічні порушення за умов інсулінорезистентності й ожиріння характеризуються розвитком ендотеліальної дисфункції та оксидативного стресу, що є предикторами виникнення кардіоваскулярних ризиків. Їх інтенсивність залежить від вуглеводного та тиреоїдного гомеостазу.

Background. The topicality of the theme is due to the significant prevalence of cardiovascular diseases and an increase in costs for medical care, the high risk of disability, which characterizes the medical and social component of the problem. Pathological changes can be a manifestation not only of a cardiovascular disorder, but also develop as a result of other diseases, including diabetes mellitus, obesity, and thyroid pathology. One of the main mechanisms of morbidity and mortality is macrovascular complications that can occur in endothelial dysfunction and oxidative stress. The purpose of the research is to study the peculiarities of changes in the parame­ters of the endothelial system and oxidant status in animals with insulin resistance and obesity under conditions of adequate iodine supply and iodine deficiency. Materials and methods. Study included 75 sexually mature rats having received a high-carbohydrate, high-fat diet under conditions of adequate and limited iodine supply, followed by analysis of markers of carbohydrate metabolism, thyroid status, indices of endothelial function, lipid peroxidation and antioxidant protection. Results. The development of insulin resistance and obesity in a diet loaded with fructose and fats is accompanied by the development of endothelial dysfunction: in the blood serum, the level of endothelin-1 increases and inducible NO-synthase (iNO-synthase) is activated, in the myocardium, the activity of iNO-synthase increases compared to the data in animals who received a standard diet. The development of oxidative stress in experimental animals characterizes an increase in the content of diene conjugates and thiobarbituric acid-reactive substances in blood serum and myocardium against the background of inhibition of serum antioxidant enzymes (catalase, superoxide dismutase, ceruloplasmin, glutathione peroxidase, glutathione reductase). The degree of endothelial dysfunction and the intensity of lipoperoxidation increase with hypothyroid dysfunction against the background of iodine deficiency. Conclusions. Metabolic disorders under the conditions of insulin resistance and obesity are characterized by the development of endothelial dysfunction and oxidative stress, which are the predictors of the development of cardiovascular risks. Their intensity depends on carbohydrate and thyroid homeostasis.


Ключевые слова

серцево-судинна система; інсулінорезистентність; ожиріння; тиреоїдний гомеостаз; ендотеліальна дисфункція; про-/антиоксидантна система

cardiovascular system; insulin resistance; obesity; thyroid homeostasis; endothelial dysfunction; pro-/antioxidant system

doi: http://dx.doi.org/10.22141/2224-0721.19.2.2023.1255

Introduction

Cardiovascular diseases (CVD) take a central place in the structure of morbidity and mortality, especially in the developed countries of the world. Significant rejuvenation and rapid growth of pathologies of the circulatory system lead to invalidation of the working age population [1]. Among the total number of deaths in the world, one third (about 18 million) per year is caused by CVD [2]. Over the last decade, there has been an increase in diseases of the circulatory system under the age of 55, especially in women. The same tendency persists in Ukraine [3]. Over the past thirty years, mortality because of CVD has doubled and in 2019 (before the coronavirus pandemic) took first place in terms of years of potential life, lost due to premature death from cardiac pathologies [4]. The development and course of diseases of the circulatory system are closely interrelated with risk factors, among which a significant role belongs to the comorbid pathology, including quite common diabetes mellitus (DM), obesity, and hypothyroidism [5, 6]. According to the International Diabetes Federation, more than 400 million people suffer from DM, and according to scientists’ forecasts, it is expected to increase up to 600 million over the next twenty years [7]. At the same time, 200 million people have been diagnosed with impaired glucose tolerance [8].
An important factor contributing to the formation of insulin resistance (IR) is obesity. Excessive accumulation of adipose tissue can increase the risk of complications [9]. Currently, the prevalence of overweight has reached pandemic proportions and becomes a socio-economic burden for modern society [10]. On the basis of clinical and experimental studies, it has been found that excessive body weight is one of the probable triggers for the CVD development, and the degree of cardiovascular risk depends on the distribution of adipose tissue and is especially high in central obesity [11, 12]. Disturbance of thyroid homeostasis can be an aggravating factor of these endocrine diseases. It is important that more than 30 % of the population of 50 world countries live in goiter endemic regions, and in Ukraine over the last decade the number of cases of thyroid pathology has increased from 689 thousand to 1 million 846 thousand cases [13].
Vascular diseases are the main cause of disability and mortality in patients with DM and excessive body weight [14]. It is known that hyperglycemia positively correlates with vascular complications, and impaired glucose tolerance can cause a high risk of developing coronary events. Although their pathogenetic mechanisms are complex, excessive production of reactive oxygen species plays an important role [15]. The aggressive influence of free radicals is especially dangerous when the body’s antioxidant reserves are simultaneously inhibited. Another negative factor affecting the oxidant status is a violation of the balance between vasodilation and vasoconstriction, inhibition and promotion of proliferation, anti- and prothrombotic homeostasis, which characterizes the development of endothelial dysfunction [16].
The most powerful vasoconstrictor in the body is endothelin, released out of the damaged endothelium [17]. Endothelial enzymes (isoforms of NO-synthase) from L-arginine, by reducing inorganic nitrates, form the endogenous vasodilator nitric oxide [18]. The complex mechanism of formation of endothelial dysfunction can be already triggered at the stage of prediabetes, minimal thyroid insufficiency and excessive body weight. Therefore, its early detection will contribute to the timely prevention of the development and progression of CVD and their complications.
The purpose of the research is to study the peculiarities of changes in the parameters of the endothelial system and oxidant status in animals with IR and obesity under conditions of adequate iodine supply and iodine deficiency.

Materials and methods

Experimental studies included non-linear male rats weighing 150–180 g (n = 75), randomized by the method of accidental sampling. The animals were divided into the following groups: group 1 — control (intact animals, n = 15), group 2 — animals with IR under conditions of adequate iodine supply (n = 15), group 3 — animals with obesity under conditions of adequate iodine supply (n = 15), group 4 — IR animals under conditions of iodine deficiency and group 5 — animals with obesity under conditions of iodine deficiency (n = 15). The control group included intact animals kept under the conditions of a standard food ration, the usual temperature and light regime of the vivarium.
In order to simulate the development of IR (groups 2 and 4), animals received 10% fructose solution instead of drinking water for eight weeks [19]. To reproduce obesity (groups 3 and 5), rats were kept on a high-fat diet during the experiment (eight weeks). Animals in groups 4 and 5 were kept on an iodine-deficient diet during the same period. Carbohydrate metabolism was characterized by the content of insulin in the blood serum, glycated hemoglobin (HbA1c) and the blood glucose concentration. The development of IR was assessed by the values of the HOMA-IR (Homeostasis Model Assessment Insulin Resistance) index. The content of insulin in the blood serum was determined by the enzyme-linked immunosorbent assay (ELISA) using a set of reagents EIA-2935 (Elabscience, USA) using a tablet analyzer Stat Fax 2100 (China).
The concentration of glucose in the blood was determined by the glucose-oxidizing method using reagents from the LLC RPE “Filisit-Diahnostyka” (Dnipro, Ukraine). The content of HbA1c in whole blood was determined by the reaction with thiobarbituric acid (TBA) using a standard set of reagents of LLC RPE “Filisit-Diahnostyka” LLC (Dnipro, Ukraine). Control over the reproduction of obesity was performed by weighing the animals, measuring the nasal-anal length and calculating the body mass index (BMI). Body weight gain was estimated in percents and characterized as follows: with an increase at 10–25 %, obesity was considered mild; with an increase at 26–40 % — moderate severity; with an increase of more than 40 % — severe.
BMI was calculated according to the formula: BMI (g/cm2) = m / l2, where m — is the body mass (g); l — body length (cm). To assess the thyroid status of animals, the content of free triiodothyronine (fT3) and thyroxine (fT4), thyroid-stimulating hormone (TSH) in blood serum was studied, followed by the calculation of fT3/fT4, TSH/fT4 indices. The level of hormones of the pituitary-thyroid axis was determined by enzyme immunoassay using the ELISA kit (Elabscience, USA). The condition of iodine supply of rats was assessed by the concentration of iodine in daily portions of urine, which was collected using metabolic cages.
The state of endothelial function was studied by the content of ET-1 level in blood serum, iNOS activity in blood serum and myocardium. ET-1 content was determined by enzyme immunoassay using Biomedica (Austria) reagents. The activity of iNOS was investigated by immunoenzymatic method using the reagents “Rat NOS2/iNOS (Nitric Oxide Synthase 2, Inducible) ELISA Kit” (Elabscience, USA). The intensity of the processes of lipid peroxidation was characterized by the accumulation of diene conjugates (DC) and thiobarbituric acid-reactive products (TBA-AP) in blood serum and myocardium. The state of the antioxidant system was determined by the activity of catalase, superoxide dismutase (SOD), glutathione peroxidase (GP), glutathione reductase (GR), the content of ceruloplasmin (CP) in blood serum.
Statistical analysis of the results was performed using Microsoft Excel and Statistica 5.5 (Multiple Regression) computer programs using variational statistics methods. For each of the samples, it was checked whether the distribution of the studied indices was normal using the Kolmogorov-Smirnov, Lilliefors tests. The obtained data conformed to the Gaussian law, so the results are represented by the M ± m interval. The significance of the differences was assessed according to the Student’s t-test. A value of p < 0.05 was considered reliable.
According to the decision of the ethics committee in the Ivano-Frankivsk National Medical University of the Ministry of Health of Ukraine (protocol No. 123/21 dated 09/21/2021), it was determined that the performed studies fully comply with the main provisions of the Rules for Conducting Work Using Laboratory Animals (1977). The conditions of keeping and manipulation of the animals during the research, the removal of the rats out of the experiment met the requirements of the legislation of Ukraine (Law of Ukraine No. 3447-IV “On the Protection of Animals from Cruelty Treatment”, 2006), Order of the Ministry of Health of Ukraine No. 281 dated November 1, 2000 “On measures for the further improvement of organizational norms of work with the use of experimental animals” and the principles of the European Convention on the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (Strasbourg, 1986).

Results

As a result of the study, the development of IR was observed in animals receiving a high-carbohydrate diet under the conditions of adequate iodine supply and iodine deficiency (groups 2 and 4), which is confirmed by changes in carbohydrate metabolism indices. At the same time, the HOMA-IR index in animals of these experimental groups exceeded the data of intact animals at 94.0 % (р1–2 < 0.001) and 2.5-fold (р1–4 < 0.001), respectively (Table 1). In group 3, the changes in indices of carbohydrate metabolism were less pronounced, and the HOMA-IR index exceeded the value of animals following a standard diet at 64.1 % (р1–3 < 0.01).
Keeping rats on an iodine-deficient diet (groups 4 and 5) led to the development of hypothyroid dysfunction (a decrease in the level of fT3 and fT4 at 23.9–64.1 % (р1–4, 1–5 < 0.01), and an increase in TSH at 30.8–61.5 % (р1–4, 1–5 < 0.01) relative to the data in intact animals). Such changes occurred against the background of a decrease in iodine excretion with urine (Table 2).
During the experiment, an increase in BMI was found in animals of all groups at 32.6–71.7 % (р < 0.01) compared to the control. The development of moderate obesity in conditions of a high-fructose diet and the heavy one — on the background of a high-fat diet, regardless of thyroid homeostasis.
In isolated IR (group 2), a 2.4-fold (р1–2 < 0.01) increase in the level of ET-1 and a 3.5-fold (р1–2 < 0.001) increase in the activity of iNOS were observed in blood serum compared to similar indices of intact rats, which characterizes the development of endothelial dysfunction. Under these conditions, a 2.5-fold (р1–2 < 0.001) activation of iNOS was detected in the myocardium compared to the control. In IR on the background of hypothyroid dysfunction (group 4), the level of ET-1 in the blood serum increased threefold (р1–4 < 0.001) and the activity of iNOS increased 4.3-fold (р1–4 < 0.001), in the myocardium — iNOS was activated 2.7-fold (р1–4 < 0.001) compared to control data (Table 3).
The development of IR was accompanied by the activation of free radical processes. In particular, in the blood serum and myocardium of rats receiving a high-fructose diet, the content of DC and TBA-AP increased at 79.7 % — 2.1-fold (р1–2 < 0.05) compared to the initial data. In the animals kept on a combined diet (group 4), the content of lipid peroxidation products in the examined tissues exceeded the control data at 76.9 % — fourfold (р1–4 < 0.05). Simultaneously with the activation of lipoperoxidation processes, multidirectional changes in the activity of antioxidant enzymes were observed in experimental animals. In rats with isolated IR, inhibition of catalase at 69.4 % (p1–2 < 0.01), SOD — at 35.4 % (p1–2 < 0.05), and a decrease in the content of CP in blood serum at 59.3 % (p1–2 < 0.05) with a simultaneous increase in the activity of GP and GR at 52.4 and 66.7 % (p1–2 < 0.05) were determined with respect to similar data of the control group (Table 5). Fructose loading during iodine deprivation leads to unidirectional changes in the antioxidant system, but there is a tendency to depletion of the antioxidant reserve.
In the animals of group 3, under the conditions of obesity, a 2.3-fold (p1–3 < 0.001) increase in ET-1 content in the blood serum and a 2.8-fold (p1–3 < 0.001) increase in iNOS activation were observed compared to the data in intact rats. At the same time, in the myocardium of animals, an increase in the activity of iNOS was found two times (p1–3 < 0.001) compared to the control. Obesity against the background of iodine deficiency has led to a 2.5-fold (p1–5 < 0.001), increase in the level of ET-1, a 3.9-fold (p1–5 < 0.001) increase in the activation of iNOS in blood serum, and a 2.5-fold (p1–5 < 0.001) increase in the activity of iNOS in the myocardium compared to the parameters of the intact group.
In the blood serum and myocardium of animals of group 3, an increase in DC content at 38.5–74.5 % (p1–3 < 0.05) compared to the data in animals of the control group was found. More significant changes in lipid peroxidation indices were found in IR under the conditions of iodine deprivation (the content of DC and TBA-AP in the examined tissues has increased at 59.0 % — 2.7-fold, p1–5 < 0.05). The development of obesity has led to a decrease in the activity of the studied antioxidant enzymes at 33.5–62.3 % (p1–3 < 0.05) compared to the data in animals with the appropriate BMI. More pronounced changes in the antioxidant reserve were found in obesity under conditions of iodine deprivation (decrease in the activity of antioxidant enzymes at 39.2–65.6 % (p1–5 < 0.05) compared to similar data of the control group).

Discussion

As a result of the study, it was determined that fructose loading with adequate or limited iodine supply leads to the development of endothelial dysfunction, especially in combined endocrinopathy (IR in combination with hypothyroid dysfunction). It is known that ET-1 has a significant vasoconstrictive effect, pro-inflammatory and proliferative properties. ET-1 indirectly affects the main links of diabetic complications and dysfunction of the cardiovascular system, because endotheliocytes are the first targets that are damaged under the influence of hyperglycemia [20]. According to experimental and clinical studies, in the absence of functional B-type endothelin receptors, the level of insulin in blood serum decreases and glucose tolerance increases [21].
Activation of iNOS in IR, especially under conditions of iodine deprivation, may reflect the peculiarities of the immune response, the development of inflammation, and pathological processes (increase in glycosylation end products, activation of protein kinase, polyol, and hexamine pathways of glucose metabolism). Such mechanisms are accompanied by the development of oxidative stress, because the early trigger of endothelial dysfunction is an imbalance between the accumulation of the active oxygen forms and the bioavailability of NO. It is known that if the iNOS gene of diabetic rats is transferred into intact arteries, then NO-dependent vasodilation is damaged, which characterizes the development of endothelial dysfunction [22]. It is likely that the NO-synthase pathway of L-arginine metabolism is activated in experimental animals, which leads to an increase in the activity of iNOS in diabetes mellitus, which, under conditions of oxidative stress, can turn into compounds toxic to the body, in particular, peroxynitrite, dinitrogen trioxide, nitrates and nitrites [23].
In response to the intense development of oxidative stress when glucose tolerance is impaired, the antioxidant system reacts, because the toxic effect of products in cells is due to the fact that oxidized proteins and lipids are a source of free radicals that deplete the reserves of cellular antioxidants [24]. As a result of the analysis of the data obtained, multidirectional changes in antioxidant defense enzymes were determined in animals with IR. This reaction of enzymes against free radicals under the influence of oxidative stress is natural, because catalase and SOD belong to the first line of defense. Excessive intensity of nitroso-oxidative reactions is associated not only with a decrease in the activity of the antioxidant system, but also with decompensation of carbohydrate metabolism [25]. Therefore, the detected antioxidant imbalance may indicate a greater probability of damage to myocardial tissue and blood vessels under conditions of IR.
Changes in the parameters of endothelial function in obese animals, found during the study, reflect a high risk of developing vascular disorders, because a significant increase in ET-1 can be a consequence of the inflammatory process, the progression of oxidative stress, excessive production of cytokines and stimulation of the generation of free radicals. Under the conditions of excessive body weight, adipose tissue and its adipokine are important for the development of endothelial dysfunction, because under such conditions, inflammatory processes are activated, which directly or indirectly depend on the substances it synthesizes [26, 27]. Thus, an increased amount of reactive oxygen species causes cell damage and death, and oxidative stress increases the permeability of the vascular endothelium and leads to the adhesion of leukocytes [28]. Activation of iNOS under conditions of exposure to obesity may be a consequence of excessive synthesis of NO in response to inflammation.
Simultaneously with the development of oxidative stress due to the activation of lipoperoxidation processes in animals with excessive body weight, inhibition of the activity of catalase, GP and GR was found against the background of SOD activation. Such dynamics is regarded as a reaction to the formation of a large number of free radicals, which correlates with an excessive increase in body weight.

Conclusions

High-carbohydrate and high-fat diets in animals predispose to the development of IR and obesity, which leads to the development of endothelial dysfunction and oxidative stress, which are potentiated under conditions of iodine deprivation and the development of hypothyroid dysfunction. Such processes can cause damage to blood vessels and myocardial tissues, and act as triggers for the development of cardiovascular pathology.
 
Received 08.12.2022
Revised 07.02.2023
Accepted 01.03.2023

Список литературы

  1. Kobrynska O.Ya., Didushko O.M. Current possibilities of influencing the main cardiovascular risk factors in patients with type 2 diabetes mellitus. International Journal of Endocrinology (Ukraine). 2022. 18(8). 426-31. doi: 10.22141/2224-0721.18.8.2022.1220.
  2. Vardas P.E., Asselbergs F.W., van Smeden M., Friedman P. The year in cardiovascular medicine 2021: digital health and innovation. Eur. Heart J. 2022. 43(4). 271-9. doi: 10.1093/eurheartj/ehab874.
  3. Aksenov E.V. Endothelial Dysfunction and Ways of its Prevention during Percutaneous Coronary Interventions by Recanalization of Coronary Arteries. Ukrainian Journal of Medicine, Biology and Sport. 2019. 4(5). 102-8. doi: 10.26693/jmbs04.05.102 (in Ukrainian).
  4. Sirenko Yu.M. The state of the problem of cardiovascular morbidity and mortality in Ukraine. Medicine of Ukraine. 2022. 2(258). 11-4. doi: 10.37987/1997-9894.2022.2(258).264084 (in Ukrainian).
  5. Cosentino F., Bhatt D.L., Marx N., Verma S. The year in cardiovascular medicine 2021: diabetes and metabolic disorders. Eur. Heart J. 2022. 43(4). 263-70. doi: 10.1093/eurheartj/ehab876.
  6. Pankiv V.I., Yuzvenko T.Yu., Pankiv I.V. Type 2 diabetes mellitus and subclinical hypothyroidism: focusing on the role of cholecalciferol. Problems of Endocrine Pathology. 2019. 2. 46-51. doi: 10.21856/j-PEP.2019.2.07.
  7. Sun H., Saeedi P., Karuranga S., Pinkepank M., Ogurtsova K., Duncan B.B., Stein C. et al. IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pract. 2022 Jan. 183. 109119. doi: 10.1016/j.diabres.2021.109119.
  8. Eades C.E., France E.F., Evans J.M. Prevalence of impaired glucose regulation in Europe: a meta-analysis. Eur. J. Public Health. 2016 Aug. 26(4). 699-706. doi: 10.1093/eurpub/ckw085.
  9. Lin X., Li H. Obesity: Epidemiology, Pathophysiology, and Therapeutics. Front. Endocrinol. (Lausanne). 2021 Sep 6. 12. 706978. doi: 10.3389/fendo.2021.706978.
  10. Chooi Y.C., Ding C., Magkos F. The epidemiology of obesity. Metabolism. 2019 Mar. 92. 6-10. doi: 10.1016/j.metabol.2018.09.005.
  11. Dinets A.V., Gorobeiko M.B., Zdorna V.V., Hoperia V.H., Lovin A.V. An integrated approach for obesity management: the effectiveness of glucagon-like peptide 1 agonist and life-style interventions for obesity management. International Journal of Endocrinology (Ukraine). 2022. 18(3). 12-9. doi: 10.22141/2224-0721.18.3.2022.1161 (in Ukrainian).
  12. Di Daniele N., Tesauro M., Mascali A., Rovella V., Scuteri A. Lower Heart Rate Variability Is Associated with Lower Pulse Pressure Amplification: Role of Obesity. Pulse (Basel). 2018. 5(1–4). 99-105. doi: 10.1159/000479701.
  13. Kamyshna І.І., Pavlovych L.B., Maslyanko V.A., Chornenka Zh.A. Epidemiological assessment of dynamics of the prevalence and incidence of the thyroid gland diseases in Ukraine and Chernivtsi region. Clinical and Experimental Pathology. 2021. 20(3). 75-81. doi: 10.24061/1727-4338.XX.3.77.2021.11.
  14. Liu R., Li L., Shao C., Cai H., Wang Z. The Impact of Diabetes on Vascular Disease: Progress from the Perspective of Epidemics and Treatments. J. Diabetes Res. 2022. 2022. 1531289. doi: 10.1155/2022/1531289.
  15. Turchina S.I., Shushlyapina E.V., Kosovtsova A.V., Shlya–khova N.V. Thyroid Dysfunction and Childhood Obesity (literature review and own research). Modern Pediatrics. Ukraine. 2020. 2(106). 56-62. doi: 10.15574/SP.2020.106.56.
  16. Gallo G., Volpe M., Savoia C. Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications. Front. Med. (Lausanne). 2022 Jan 20. 8. 798958. doi: 10.3389/fmed.2021.798958.
  17. Poredos P., Poredos A.V., Gregoric I. Endothelial Dysfunction and Its Clinical Implications. Angiology. 2021 Aug. 72(7). 604-615. doi: 10.1177/0003319720987752.
  18. Kröller-Schön S., Daiber A., Steven S., Oelze M., Frenis K., Kalinovic S. et al. Crucial role for Nox2 and sleep deprivation in aircraft noise-induced vascular and cerebral oxidative stress, inflammation, and gene regulation. Eur. Heart J. 2018. 39(38). 3528-39. doi: 10.1093/eurheartj/ehy333.
  19. Todoriv T.V., Bagrii M.M., Voronych-Semchenko N.M. State of endothelial function, lipid spectrum and features of coronary vessels structure of rats with obesity and insulin resistance under iodine deficiency conditions. Fiziolohichnyi zhurnal. 2021. 67(6). 21-31. doi: 10.15407/fz67.06.021.
  20. Malevych N.M., Yaroshenko T.Ya. Impact of acute hypoxic hypoxia on the oxidative and non-oxidative phases of l-arginine metabolism in myocardium and aorta of rats in age aspect. Medical and Clinical Chemistry. 2021. 23(2). 41-47. doi: 10.11603/mcch.2410-681X.2021.i2.12237.
  21. Maguire J.J., Davenport A.P. Endothelin receptors and their antagonists. Semin. Nephrol. 2015 Mar. 35(2). 125-36. doi: 10.1016/j.semnephrol.2015.02.002.
  22. Asanov E.O., Gavalko A.V., Duzhak G.V., Naskalova S.S., Antonyuk-Shcheglova І.А., Shatilo V.B. Microcirculation and vasomotor function of the endothelium in elderly people with impaired glucose tolerance. Fiziolohichnyi zhurnal. 2022. 68(4). 28-32. doi: 10.15407/fz68.04.028 (in Ukrainian).
  23. Ouerd S., Idris-Khodja N., Trindade M., Ferreira N.S., Berillo O., Coelho S.C. et al. Endothelium-restricted endothelin-1 overexpression in type 1 diabetes worsens atherosclerosis and immune cell infiltration via NOX1. Cardiovasc. Res. 2021. 117(4). 1144-53. doi: 10.1093/cvr/cvaa168.
  24. Zhou S.S., Jin J.P., Wang J.Q., Zhang Z.G., Freedman J.H., Zheng Y. et al. miRNAS in cardiovascular diseases: potential biomar–kers, therapeutic targets and challenges. Acta Pharmacol. Sin. 2018. 39(7). 1073-84. doi: 10.1038/aps.2018.30.
  25. Danylovych Yu.V., Danylovych H.V., Kosterin S.O. Рossible importance of adenylate cyclase signaling pathway in the synthesis of nitric oxide by myometrium mitochondria. Fiziolohichnyi zhurnal. 2022. 68(4). 33-9. doi: 10.15407/fz68.04.033 (in Ukrainian).
  26. Bilovol O.M., Kniazkova I.I., Bohun M.V., Kuzminova N.V., Osovska N.Y. Treatment of heart failure in patients with diabetes mellitus. World of Medicine and Biology. 2020. 1(71). 18-22. doi: 10.26724/2079-8334-2020-1-71-18-22.
  27. Voloshchuk O.M., Kopylchuk Н.P. Intensity of free radical processes in rat skeletal muscles under the conditions of different dietary supply with nutrients. Fiziolohichnyi zhurnal. 2022. 68(4). 48-56. doi: 10.15407/fz68.04.048 (in Ukrainian).
  28. Sorokman T.V., Popeliuk N.O. Obesity in children: criteria for predicting the development of hypertension. International Journal of Endocrinology (Ukraine). 2020. 16(2). 66-72. doi: 10.22141/2224-0721.16.2.2020.201299 (in Ukrainian).

Вернуться к номеру