Discovery of the Phenomenon of Intracellular Development of Cardiac Stem Cell: A New Step in Understanding of Biology and Behavior of Tissue-Specific Stem Cells

In our experiments with an in vitro culture of rat cardiac cells, we identified and described for the first time the phenomenon of intracellular development of CSCs in mature CMs with formation of the “cell-in-cell structures” (CICSs). Recently, we have confirmed the reproducibility of our results and existence of this phenomenon in rats of different age groups, 1-year-old bull, adult mice and humans. Moreover, we demonstrated the 5–10 times increase in the amount of CICSs after exposure of in vitro cultures to hypoxia and acidosis, that is, these conditions stimulate intracellular development of CSCs. Our data strongly suggest that transitory amplifying cells (TACs), which release from CICSs, are present as a very rare cell population in adult and old rats. Therefore, we assume that TACs are important for renewal of myocardium during ontogenesis. TACs should be considered as the major source of cells that can reduce myocardial damage in adult mammals with various pathologies of the cardiovascular system. In conclusion, precise and exhaustive analysis of the phenomenon of intracellular development of CSCs, CICSs and TACs will pave the way for cell technologies of new generation in regenerative medicine

ПОВЫШЕНИЕ УРОВНЯ ПРОВОСПАЛИТЕЛЬНЫХ ЦИТОКИНОВ В ПЛАЗМЕ КРОВИ У ПАЦИЕНТОВ С ХРОНИЧЕСКОЙ ТРОМБОЭМБОЛИЧЕСКОЙ ЛЕГОЧНОЙ ГИПЕРТЕНЗИЕЙ

HighlightsIL-8 and MCP-1 have a significant role in the CTEPH pathogenesis, which indicates the importance of nonspecific immunity in the formation and progression of CTEPH. The coupling between cytokines and hemodynamic parameters, cardiac structural changes and plasma biochemical parameters were determined. AbstractBackground. Chronic thromboembolic pulmonary hypertension (CTEPH) pathogenesis is complex and not fully understood. Particular attention to the microvascular damage genesis in CTEPH is given to aseptic inflammation, which in turn could be mediated through various molecular mechanisms. According to the conflicting and incomplete data on changes in the profile of factors controlling inflammation in CTEPH, research in this field would identify new therapeutic targets for the prevention and treatment of CTEPH.Aim. To study the profile of plasma proinflammatory cytokines in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and evaluate the coupling of these cytokines with the main morphofunctional and laboratory values of the disease severity.Methods. 34 patients with CTEPH were included in this study. To characterize the group, the following methods were used: echocardiographic examination, catheterization of the right cardiac chambers. Biomarkers of heart failure, systemic inflammation, as well as erythropoiesis and iron metabolism were assessed in all patients. The control group included 10 donors. To study the proinflammatory cytokine profile in plasma, interleukins (IL) 6, 8, 18, monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase 9 were determined using standard enzyme-linked immunosorbent assay (ELISA) kits.Results. Hemodynamic and morphofunctional changes in the pulmonary circulation specific to pulmonary hypertension were determined with catheterization of the right cardiac chambers and echocardiography. During plasma proinflammatory cytokines analysis, a significant increase in the level of IL-8 (p = 0.030) and MCP-1 (p = 0.031) in CTEPH group compared to the control group was observed. No significant differences for other analyzed markers were found. In the elaboration of the correlation analysis, moderate inverse coupling between proinflammatory markers and hemodynamic parameters characterizing the CTEPH severity were revealed, as well as positive correlations with parameters of remodeling of the right cardiac chambers and iron metabolism.Conclusion. The increased levels of IL-8 and MCP-1 in patients with CTEPH identified in the present study indicate a significant role of nonspecific immunity in the formation and progression of CTEPH. The coupling between cytokines and hemodynamic parameters, structural cardiac changes and plasma biochemical parameters were determined. Based on the obtained data, it is possible to develop new medicinal substances, targeting towards proinflammatory cytokines, their receptors and signaling pathways.Основные положенияИЛ-8 и MCP-1 играют существенную роль в патогенезе хронической тромбоэмболической легочной гипертензии, что указывает на важное значение неспецифического иммунитета в формировании и прогрессировании данного заболевания. Определена связь цитокинов с показателями гемодинамики, структурными изменениями сердца и биохимическими показателями плазмы крови. РезюмеАктуальность. Патогенез хронической тромбоэмболической легочной гипертензии (ХТЭЛГ) сложен и до конца не изучен. Особое внимание в генезе микрососудистого поражения при ХТЭЛГ уделяют асептическому воспалению, которое в свою очередь может быть опосредовано различными молекулярными механизмами. Учитывая противоречивые и неполные данные об изменении профиля факторов, контролирующих воспаление при ХТЭЛГ, исследования в этой области позволят определить новые терапевтические мишени для профилактики и лечения ХТЭЛГ.Цель. Изучить профиль провоспалительных цитокинов в плазме крови у пациентов с ХТЭЛГ и оценить связь этих цитокинов с основными морфофункциональными и лабораторными показателями тяжести течения заболевания.Материалы и методы. В исследование включены 34 пациента с верифицированным диагнозом ХТЭЛГ. Для характеризации группы использованы эхокардиографическое исследование и катетеризация правых камер сердца. У всех больных оценены биомаркеры сердечной недостаточности, системного воспаления, а также эритропоэза и обмена железа. В группу контроля вошли 10 человек-доноров. Для изучения профиля провоспалительных цитокинов в плазме крови определены интерлейкины (ИЛ) 6, 8, 18, моноцитарный хемоаттрактантный белкок 1 (MCP-1) и матриксная металлопротеиназа 9 с помощью стандартных наборов для иммуноферментного анализа.Результаты. По данным катетеризации правых камер сердца и эхокардиографии определены гемодинамические и морфофункциональные изменения малого круга кровообращения, характерные для легочной гипертензии. При анализе уровня провоспалительных цитокинов в плазме крови в группе ХТЭЛГ по сравнению с группой контроля отмечено значимое повышение ИЛ-8 (p = 0,030) и MCP-1 (p = 0,031). По другим проанализированным маркерам значимых различий не получено. В результате корреляционного анализа выявлены умеренные обратные взаимосвязи провоспалительных маркеров с гемодинамическими параметрами, характеризующими тяжесть ХТЭЛГ, а также положительные корреляционные связи с показателями ремоделирования правых камер сердца и обмена железа.Заключение. Установленное в настоящем исследовании повышение уровней ИЛ-8 и MCP-1 у пациентов с ХТЭЛГ указывает на значительную роль неспецифического иммунитета в формировании и прогрессировании ХТЭЛГ. Определены взаимосвязи цитокинов с показателями гемодинамики, структурными изменениями сердца и биохимическими показателями плазмы крови. На основе полученных данных возможна разработка новых лекарственных субстанций, мишенями для которых будут провоспалительные цитокины, их рецепторы и сигнальные пути

Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery

To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research

Arterial baroreceptor reflex counteracts long-term blood pressure increase in the rat model of renovascular hypertension.

INTRODUCTION: The present study tested the hypothesis that long-term effects of baroreceptor activation might contribute to the prevention of persistent arterial blood pressure (BP) increase in the rat model of renovascular hypertension (HTN). METHODS: Repetitive arterial baroreflex (BR) testing was performed in normo- and hypertensive rats. The relationship between initial arterial BR sensitivity and severity of subsequently induced two-kidney one-clip (2K1C) renovascular HTN was studied in Wistar rats. Additionally, the time course of changes in systolic BP (SBP) and cardiac beat-to-beat (RR) interval was studied for 8 weeks after the induction of 2K1C renovascular HTN in the rats with and without sinoaortic denervation (SAD). In a separate experimental series, cervical sympathetic nerve activity (cSNA) was assessed in controls, 2K1C rats, WKY rats, and SHR. RESULTS: The inverse correlation between arterial BR sensitivity and BP was observed in the hypertensive rats during repetitive arterial BR testing. The animals with greater initial arterial BR sensitivity developed lower BP values after renal artery clipping than those with lower initial arterial BR sensitivity. BP elevation during the first 8 weeks of renal artery clipping in 2K1C rats was associated with decreased sensitivity of arterial BR. Although SAD itself resulted only in greater BP variability but not in persistent BP rise, the subsequent renal artery clipping invariably resulted in the development of sustained HTN. The time to onset of HTN was found to be shorter in the rats with SAD than in those with intact baroreceptors. cSNA was significantly greater in the 2K1C rats than in controls. CONCLUSIONS: Arterial BR appears to be an important mechanism of long-term regulation of BP, and is believed to be involved in the prevention of BP rise in the rat model of renovascular HTN

Effect of Physical Training on the Morphology of Parasympathetic Atrial Ganglia after Unilateral Vagotomy in Rats

Cardiac denervation is a serious problem in a number of patients, including patients after heart transplantation. The status of the parasympathetic ganglia after crossing the preganglionic fibers of the vagus nerve has not been enough studied. The aim of our study was to assess the effect of physical training on the morphological parameters of the parasympathetic atrial ganglia and autonomic regulation of heart rate after right- and left-sided vagotomy in rats. Morphometric characteristics of the right atrial ganglia were evaluated using an immunohistochemical method after a study that included a three-time assessment of heart rate variability. It was found that right-sided vagotomy leads to both an increase in the volume of ganglion and autonomic dysfunction. No significant change in the number of nerve cells was found in animals with false and left-sided vagotomy while maintaining preganglionic innervation after the physical training, whereas exercises led to a decrease in the volume of nerve tissue of rats with right-sided denervation. It was also found that in animals with preserved vagal innervation, the volume of atrial ganglion tissue correlates with overall heart rate variability and a normalized parasympathetic component. Therefore, a positive effect from regular physical activity on parasympathetic regulation can be expected only if preganglionic vagal influence is preserved

The relationship between baroreflex (BR) sensitivity and systolic blood pressure (SBP) in the pooled samples of Wistar rats with stable hypertension (n = 10) and without hypertension (n = 10) 8 weeks after induction of two-kidney one-clip renovascular hypertension.

<p>The inverse correlation between BR sensitivity and SBP is observed (r = 0.69, <i>p</i><0.01).</p

Indocyanine Green-Containing Magnetic Liposomes for Constant Magnetic Field-Guided Targeted Delivery and Theranostics

The aim of the present study was to develop magnetic liposomes (MLPSs) incorporating an agent with the ability to act both as a photosensitizer and as a fluorophore for optical imaging. We therefore aimed to develop a preparation method for indocyanine green (ICG)-containing MLPS, followed by a detailed characterization of their physicochemical and magnetic properties. The ability of intravenously administered ICG-containing MLPSs to accumulate in tissue exposed to a constant magnetic field was tested in vivo. Using the thin film hydration method, 170-nm aqueous liposomes containing magnetic nanoparticles and indocyanine green were synthesized, followed by a detailed characterization of their physicochemical properties. It was shown that ICG-containing MLPSs possess the properties of T2 contrast for MRI. Apart from this, ICG-containing MLPSs were clearly visualized using near infrared fluorescent imaging, which was demonstrated in in vivo experiments showing an accumulation of ICG-containing MLPSs in the zone of magnetic field distribution produced by a previously implanted constant magnet in the tissue. Although not directly tested in the present study, therapeutic applications of ICG-containing MLPSs include magnetic hyperthermia, as well as the photodynamic, photothermal, and photoacoustic effects of ICG. Taking into account the fact that liposomes, iron oxide nanoparticles, and ICG are all FDA-approved agents, it is highly likely that ICG-containing MLPSs could be successfully translated to clinical practice