Pathological cardiac hypertrophy, a major contributor to heart failure, is characterized by an abnormal increase in the size of atria and ventricles. In the context of ventricular hypertrophy, the right ventricle (RV) exhibits less resistance to hypertrophy than the left one (LV). Insulin-like growth factors (IGF-1 and IGF-2) are critical for cell growth and provide cardioprotective effects. Pregnancy-associated plasma protein-A (PAPP-A) is a protease that cleaves insulin-like growth factor-binding protein-4 (IGFBP-4) and enhances IGF bioavailability. This study investigated PAPP-A-mediated IGFBP-4 proteolysis-one possible mechanism of IGF release regulation in rat models of right ventricular (RVH) and left ventricular (LVH) hypertrophy. RVH was induced with monocrotaline, and LVH via renovascular hypertension (1 Kidney 1 Clip (1K1C) model). Systolic blood pressure was measured using tail-cuff plethysmography. Heart morphometry was used to assess the mass of cardiac chambers. Cardiomyocyte purity was confirmed via troponin I immunocytochemistry. Plasma natriuretic type-B peptide (BNP) and C-terminal IGFBP-4 (CT-IGFBP-4) concentrations were quantified by fluoroimmunoassay. RVH and LVH were successfully modelled, with 1.6-fold and 1.3-fold increases in RV (p < 0.0001) and LV masses (p < 0.05), respectively. Plasma BNP was 2-3 times higher in LVH versus control rats. Hypertrophied cardiomyocytes secreted significantly more BNP than controls, showing 3.3-fold and 4.1-fold increases in LVH and RVH, respectively. PAPP-A-mediated IGFBP-4 proteolysis was 4-fold higher in RVH compared to control, but unaffected in LVH. These findings suggest that PAPP-A-specific elevation of IGFBP-4 proteolysis occurs predominantly in RVH, suggesting a differential IGF bioavailability in both ventricles and highlighting PAPP-A as a potential target to increase RVH resistance to hypertrophy.

Astrocytes are subtypes of glial cells involved in metabolic, structural, homeostatic, and neuroprotective processes that help neurons maintain viability. Insulin-like growth factors IGF-1 and IGF-2 are known to have neuroprotective effects on neurons and glial cells through interaction with specific receptors. IGF forms a complex with IGF-binding proteins (IGFBP) in nervous tissue and is released from the complex via IGFBP proteolysis by specific proteases. It has been reported that IGFBP-2, 5 and 6 are cleaved by specific proteases in the central nervous system (CNS), followed by IGF release; however, it was unknown whether IGFBP-4 was exposed to a particular proteolysis in nervous tissue. Using neurons and astrocytes derived from human induced pluripotent stem cell lines (hiPSC), as well as rat brain-sourced primary neuron-glia cultures, we demonstrated that IGFBP-4 is specifically cleaved in nervous tissue by the Pregnancy Associated Plasma Protein A (PAPP-A) protease and that this cleavage is IGF-dependent. Our results indicate that astrocyte rather than neuron PAPP-A cleaves IGFBP-4 in nervous tissue suggesting that this may be one of the fundamental mechanisms for IGF interchange between these two types of cells.

Molecular hydrogen demonstrates antioxidant and anti-inflammatory properties. It has been shown to have a protective effect in several cardiovascular diseases. The aim of this work was to investigate the effect of breathing atmospheric air containing 4 the degree of development of monocrotaline-induced pulmonary hypertension and associated lung tissue inflammation, as well as the degree of renovascular hypertension in Wistar rats. Monocrotaline-induced pulmonary hypertension (MCT-PH) was used as a model of pulmonary circulation hypertension. Three groups of animals were used in the experiment: “Control”—animals injected with monocrotaline solvent, “MCT-Control” and “MCT-H2”—groups injected with MCT once. The “Control” and “MCT-Control” groups breathed atmospheric air for 21 days, and the “MCT-H2” group breathed air containing 4 21 days. On day 21, haemodynamic parameters were measured under urethane anesthesia and lung samples were fixed for subsequent morphological analysis. Renovascular hypertension 1R1C (RVH) was used as a model of systemic hypertension. There were two groups in the experiment: RVH-C—rats breathed atmospheric air and RVH-H2 rats breathed air containing 4 blood pressure (SBP) was measured and renal excretory function was assessed. On day 28, haemodynamic parameters were measured under urethane anesthesia. In the MCT model, hydrogen had no effect on the haemodynamic symptoms of MCT hypertension, but decreased mean blood pressure (MBP), SBP and the measured markers of connective tissue remodeling in the lungs, TGF-β1 and MMP-9, and resulted in decreased tryptase secretion and mast cell counts. In the RVG model, hydrogen breathing decreased MBP, SBP and had no effect on renal excretory function. Inhalation of 4 in both models of arterial hypertension, reduces the severity of the inflammatory process, regulates the phenotypic and functional status of mast cells and inhibits the activity of profibrotic factors in lung tissue in MCT-PH. It is likely that the central action of hydrogen is combined with its anti-inflammatory and anti-fibrotic effects.

Hydrogen is known to have selective antioxidant properties. It binds highly reactive hydroxyl radicals. The pathogenesis of the monocrotaline animal model of pulmonary hypertension is associated with oxidative stress and leads to all the symptoms of pulmonary hypertension (PH) and interstitial lung disease (ILD) associated with hypertension.The aim of this work was to study the effect of 4% hydrogen inhalations on the symptoms of PH and ILD in rats.Methods. To model monocrotaline-induced pulmonary hypertension (MCT-PH), two groups of animals received a single subcutaneous injection of monocrotaline (MCT) on day 1. The control group was injected subcutaneously with MCT solvent only. The animals receiving MCT were further divided into 2 subgroups. Subgroup 1 rats breathed room air and subgroup 2 rats breathed a mixture of room air and 4% hydrogen. The regular inhalations continued until day 21. On day 21, hemodynamic parameters were measured under urethane anesthesia, the heart and its components and the lungs were weighed, and lung tissue was preserved for morphological study.Results. The inhalation had no effect on the main cardiovascular symptoms of PH, but a positive effect on the state of the connective tissue of the lungs affected by PH was shown. The mast cell response was reduced both quantitatively and functionally. There was a decrease in tryptase expression by mast cells, with predominance of the forms without signs of degranulation. TGF-β secretion was also significantly reduced and visualized by immunopositive cells in alveolar cellular structures and vessel walls.Conclusion. Inhalation of 4% hydrogen reduces inflammation and fibrosis of lung tissue during the development of MCT-PH.

Hydrogen has been shown to exhibit selective antioxidant properties against hydroxyl radicals, and exerts antioxidant and anti-inflammatory effects. The monocrotaline-induced model of pulmonary hypertension is suitable for studying substances with antioxidant activity because oxidative stress is induced by monocrotaline. On day 1, male Wistar rats were subcutaneously injected with a water–alcohol solution of monocrotaline or a control with an only water–alcohol solution. One group of monocrotaline-injected animals was placed in a plastic box that was constantly ventilated with atmospheric air containing 4% of molecular hydrogen, and the two groups of rats, injected with monocrotaline or vehicle, were placed in boxes ventilated with atmospheric air. After 21 days, hemodynamic parameters were measured under urethane narcosis. The results showed that, although hydrogen inhalation had no effect on the main markers of pulmonary hypertension induced by monocrotaline injection, there was a reduction in systemic blood pressure due to its systolic component, and a decrease in TGF-β expression, as well as a reduction in tryptase-containing mast cells.

Objective: Excessive dietary salt intake is associated with an increased risk for hypertension. However, more research on measurement, storage and kinetics of sodium on blood pressure and sex hormones is required for dietary salt restrictions. The aim was to study the influence of gonadoectomy and stop of the high-salt diet on the development of renovascular hypertension (RVH) in female rats. Design and method: Was used the model of RVH 1 kidney 1 clip (1K1C) on female Wistar rats. All manipulations with animals were carried out according to the Council Directive 86/609/EEC principles. Gonadoectomized and normal rats of 8 weeks old (eight groups) were used. |There were two control groups: one with gonads © and one without (OvE). 4 groups out of remaining 6 groups of rats, had a high salt diet (4%).. All rats from 6 groups the Goldblatt’s (1K1C) surgery was subjected. We had two groups with RVH with normal diet (0,25 % NaCl - RVH and OvE-RVH; two groups with high salt diet - RVH-HS and OvE-RVH-HS; and two groups with high salt diet, which was stop in two weeks after the Goldblatt’s (1K1C) surgery: RVH-ChHS and OvE-RVH-ChHS. In all animals the systemic blood pressure (mBP), diastolic (dBP), systolic (sBP) pressure, left ventricular pressure (LVP) and heart rate was directly measured. Left ventricular hypertrophy (LVH) was calculated as (LVweight)/(rat b.w.)*100%. Results: In all RVH groups, with and without gonads, the systemic arterial hypertension was developed. The most level of RVH was in RVH-ChHS rats: mBP - 145,7 ± 9,5 mmHg, dBP - 123,5 ± 10,4 mmHg, LVH - 0,214 ± 0,013 %. Ovariectomy leads to significant (p < 0,05) decrease in the degree of development of RVH. In OvE-RVH-ChHS was mBP 122,2 ± 6,3 mmHg, dBP 94,0 ± 6,0 mmHg and LVH 0,182 ± 0,009 %. Conclusions: Changing the diet from high salt to normal during the development of renovascular hypertension in female rats leads to an increase in the degree of disease. This effect was not observed in gonadoectomized female rats.

The ability of the promising antioxidant and neuroprotective medicine coenzyme Q10 to penetrate the blood-brain barrier (BBB) makes it a potential agent that can influence the mitochondrial metabolism of brain cells. Its reduced form (ubiquinol) is of particular interest. It can affect the structural and functional activity of cells that form the BBB. However, the mechanisms of penetration, the drug effect on brain cells and its actions are not fully understood. The aim of our work was to study the effect of ubiquinol on regulating molecules of BBB permeability and apoptosis processes in various structures of the rat brain. The effect of coenzyme Q10 on the quantity of CD31, Pgp and CLDN5 immunopositive cells and on the level of apoptosis in sections of different parts of the rat brain after a single intravenous injection of ubiquinol at a dose of 30 mg/kg was evaluated. The results indicate that ubiquinol causes an increase in the quantity of cells carrying the CD31 marker in the entorhinal cortex within 2–24h after exposure, followed by an increase in CLDN5 within 96–192h after exposure. It is noteworthy that in the amygdala, an increase in CD31 was accompanied by a delayed decrease in CLDN5, while in the hippocampus we registered only a decrease in CLDN5. Our data on an apoptosis intensity decrease do not allow us to say what contribution to this effect is made by cerebral endotheliocytes. However, the revealed signs of intensification of angiogenesis and region-specific changes in the BBB integrity under the action of ubiquinol allow us to consider it as a promising agent for the correction of BBB dysfunction in brain diseases.

Introduction. Hypertension with left ventricular hypertrophy (LVH) is a major independent risk factor for cardiovascular-related morbidity. Diet plays an essential role in the prevention and treatment of chronic cardiovascular disease. The aim of our study was to analyze the influence of 10-week diets consisting of different high fats and carbohydrates on the myocardium in spontaneously hypertensive rats (SHR). Materials and methods. The SHR (n=34) and WKY (n=34) were randomly divided into five groups (n=6 or 7 per group). For 10 weeks, the control group was fed the standard diet; the experimental groups were fed the standard chow diet with the different fats and sucrose (11% of the calorie intake). Systolic blood pressure (SBP) was measured before the experiment and 10 weeks after by the non-invasive tail-cuff method. After the experiment, the animals were humanely sacrificed. The heart specimens after routine processing were stained with hematoxylin and eosin. We determined the thickness of the left ventricle and the number of cardiomyocyte nuclei per unit area using morphometry. Results. An increase in SBP at the end of the experiment was found in SHR animals in groups receiving trans-fat and sucrose by 10.9 mm Hg and 13.4 mm Hg, respectively. Myocardial hypertrophy was observed in the SHR Butter group. Conclusion. We found that the increased content of trans-fats and sucrose in the diet leads to an increase in SBP in spontaneously hypertensive rats; saturated fatty acids – to myocardial hypertrophy in spontaneously hypertensive rats without aggravation of systolic hypertension. In normotensive animals, no negative effect of the high-fat diet on the cardiovascular system was observed. Keywords: myocardial hypertrophy, arterial hypertension, high fat diets, palm oil, carbohydrates

Cardiovascular diseases (CVD) are among the leading causes of death and disability worldwide. Pregnancy-associated plasma protein-A (PAPP-A) is a matrix metalloprotease localized on the cell surface. One of the substrates that PAPP-A cleaves is the insulin-like growth factor binding protein-4 (IGFBP-4), a member of the family of proteins that bind insulin-like growth factor (IGF). Proteolysis of IGFBP-4 by PAPP-A occurs at a specific site resulting in formation of two proteolytic fragments – N-terminal IGFBP-4 (NT-IGFBP-4) and C-terminal IGFBP-4 (CT-IGFBP-4), and leads to the release of IGF activating various cellular processes including migration, proliferation, and cell growth. Increased levels of the proteolytic IGFBP-4 fragments correlate with the development of CVD complications and increased risk of death in patients with the coronary heart disease, acute coronary syndrome, and heart failure. However, there is no direct evidence that PAPP-A specifically cleaves IGFBP-4 in the cardiac tissue under normal and pathological conditions. In the present study, using a primary culture of rat neonatal cardiomyocytes as a model, we have demonstrated that: 1) proteolysis of IGFBP-4 by PAPP-A occurs in the conditioned medium of cardiomyocytes, 2) PAPP-A-specific IGFBP-4 proteolysis is increased when cardiomyocytes are transformed to a hypertrophic state. Thus, it can be assumed that the enhancement of IGFBP-4 cleavage by PAPP-A and hypertrophic changes in cardiomyocytes accompanying CVD are interrelated, and PAPP-A appears to be one of the activators of the IGF-dependent processes in normal and hypertrophic-state cardiomyocytes.

Selenium is an important micronutrient that is essential for the functioning of the human body. Being a component of the active center of several antioxidant enzymes selenium prevents cell injury by free radicals. Decline in selenium-containing enzymes results in progression of oxidative stress and chronic inflammation, which are considered as possible causes for the development of many cardiovascular diseases. This review focuses on mechanisms for prevention of myocardial and vascular injury through the adequate selenium supply to the body. The importance of monitoring and correction of the selenium status in appropriate patients is underlined.

Introduction: In this research, we evaluate the effect of intravenously administrated solubilized ubiquinol on 4-week monocrotalin-induced pulmonary hypertension (PH) in rats. Materials and methods: To reproduce the model, some male Wistar rats were subcutaneously injected with alcohol solution of monocrotaline 60 mg/kg and the rest – with alcohol solution (Control). Those with monocrotaline (MCT) were divided into 3 groups. They underwent intravenous administration of 1% ubiquinol solution 30 mg/kg (MCT-Ubiquinol), the vehicle (MCT-Vehicle) and saline (MCT-saline) three times on days 7, 14 and 21, depending on the group. The hemodynamic parameters were measured in anesthetized rats on day 29. Right ventricle hypertrophy, pulmonary arteries reactivity and expression of miRNA-21 and miRNA-34a were estimated after euthanasia. Results and discussion: All MCT-groups demonstrated an increase in right ventricle systolic pressure and hypertrophy in comparison with the control group. An increase in lung weight was shown in MCT-Vehicle and MCT-Saline; however, the MCT-Ubiquinol indicators did not differ from those of the Control. There was an increased vasodilatation response to acetylcholine at concentrations of 1*10-6M and 1*10-5M in MCT-Ubiquinol in contrast to the other two MCT-groups. A significantly lower level of expression of miRNA-34a was observed in MCT-Ubiquinol. Conclusion: Our findings suggest that a triple ubiquinol injection influences pulmonary changes and endothelium-depended vasodilatation, which contributes to pulmonary vascular tone and reactivity. A decrease in miRNA-34a expression in MCT-Ubiquinol group demonstrates the ubiquinol anti-inflammatory properties.

Лёгочная гипертензия (ЛГ) — прогрессирующее заболевание, вызванное повышением сопротивления лёгочных сосудов и увеличением давления в лёгочной артерии. Развитие ЛГ сопровождается гипертрофией правого желудочка сердца и дисфункцией эндотелия легочных сосудов. Изучено влияние убихинола на развитие ЛГ. В экспериментах на крысах на модели монокроталиновой формы ЛГ показано, что трёхкратное внутривенное введение солюбилизированной формы убихинола снижает степень гипертрофии правого желудочка сердца и увеличивает эндотелий-зависимое расширение изолированных сегментов легочных сосудов.

BACKGROUND: Entrcsto (TM) is a new heart failure (HF) therapy that includes the ncprilysin (NEP) inhibitor sacubitril. One of the NEP substrates is B-type natriurctic peptide (BNP); its augmentation by NEP inhibition is considered as a possible mechanism for the positive effects of Entresto. We hypothesized that the circulating products of BNP proteolysis by NEP might reflect NEP impact on the metabolism of active BNP. We suggest that NEP-based BNP cleavage at position 17-18 results in BNP ring opening and formation of a novel epitope with C-terminal Arg-17 (BNP-neo17 form). In this study, we use a specific immunoassay to explore BNP-neo17 in a rat model and HF patient plasma. METHODS: We injected BNP into rats, with or without NEP inhibition with sacubitril. BNP-neo17 in plasma samples at different time points was measured with a specific immunoassay with neglectable cross-reactivity to intact forms. BNP-neo17 and total BNP were measured in EDTA plasma samples of HF patients. RESULTS: BNP-neo17 generation in rat circulation was prevented by NEP inhibition. The maximum 13.2-fold difference in BNP-neo17 concentrations with and without sacubitril was observed at 2 min after injection. BNPneo17 concentrations in 32 HF patient EDTA plasma samples ranged from 0 to 37 pg/mL (median, 5.4; interquartile range, 0-9.1). BNP-neo17/total BNP had no correlation with total BNP concentration (with r = -0.175, P = 0.680) and showed variability among individuals. CONCLUSIONS: BNP-neo17 formation is NEP dependent. Considering that BNP-neo17 is generated from the active form of BNP by NEP, we speculate that BNP-neo17 may reflect both the NEP activity and natriuretic potential and serve for HF therapy guidance. (C) 2019 American Association for Clinical Chemistry

Изучено влияние экзогенного и эндогенного эстрадиола на реактивность изолированных сосудов малого круга кровообращения у самок крыс линии Вистар с легочной гипертензией (ЛГ). ЛГ моделировали хронической прерывистой гипобарической гипоксией (10 ч/сут, 14 дней, O2 = 10 %). Сосудосуживающий эффект серотонина изучали с помощью проточной перфузии легочной артерии 3-го порядка. Как овариоэктомия, так и введение эстрадиола (15 мкг/кг/сут 28 дней) у контрольных животных не влияли на ответ легочных сосудов на серотонин. Само развитие ЛГ также не изменяло чувствительность сосудов к серотонину. Однако величина максимального ответа на серотонин резко возрастала в 2,6 раза (p < 0,05) у овариоэктомированных самок с ЛГ по сравнению с нормоксическими животными. Экзогенный эстрадиол у овариоэктомированных самок с ЛГ уменьшал ответ сосудов на серотонин до значений контроля. По-видимому, протективный эффект эстрадиола можно объяснить уменьшением количества рецепторов к серотонину в гладких мышцах сосудов.

The literature review systematizes a lot of information on the biological effects of tocotrienols. The effects are described in more details. Vitamin E was discovered at 20s of the last century, but tocotrienols are a less studied part of it. Tocotrienols exhibit cardioprotective, lipid-lowering, antitumor, anti-inflammatory, neuroprotective properties as it has been shown by recent researches. Edible oils (e.g. palm oil, rice bran oil, barley oil, etc.) contain high level of tocotrienols. So, after extraction from plant raw materials they can be used for long-term preventive therapy of many diseases, as well as for the treatment and enhancement of the action of medicinal substances. They can also be used as functional ingredients to stabilize and extend the shelf-life of food products due to their antioxidant properties.

Исследовали влияние эндогенного и экзогенного эстрадиола на степень проявления гипоксической формы легочной гипертонии (ГЛГ) у самцов и самок крыс Вистар. Эндогенный эстрадиол уменьшал величину систолического давления в правом желудочке сердца (СПЖД) в норме у самок, но не у самцов. Экзогенный 17β-эстрадиол (15 мкг/кг в течение 4 недель) воспроизводил этот эффект. ГЛГ моделировали прерывистым действием гипобарической гипоксии (10 ч в сут, О2 = 10 %). Увеличение СПЖД в большей степени развивалось у самок по сравнению с самцами. Сравнение величин СПЖД у гипертензивных самок с нормотензивными показало, что патология в большей степени развивается в группе гипертензивных самок с сохраненными яичниками, по сравнению с гонадэктомированными животными. Экзогенный 17β-эстрадиол у гипоксических овариэктомированных самок крыс Вистар не оказывал протективного действия. У самцов гонадоэктомия не оказывала действия на величину СПЖД, но вызывала развитие гипертрофии правого желудочка сердца. Экзогенный 17β-эстрадиол вызывал в этом случае увеличение величины СПЖД. Таким образом, эндогенный эстрадиол оказывает протективное действие на кровоснабжение легких у самок в норме. В случае гипоксической формы легочной гипертонии эндогенный эстрадиол усиливает развитие этой патологии у самок и гонадоэктомированных самцов.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)