The Effect of Metformin on the Myocardial Tolerance to Ischemia-Reperfusion Injury in the Rat Model of Diabetes Mellitus Type II

In recent years, evidence has been accumulated that metformin, an antidiabetic drug in the biguanide class, in addition to its well-recognized glucose-lowering effect, can also reduce cardiovascular mortality in the patients with type 2 diabetes mellitus (T2DM). Besides, there are a few experimental studies on the possibility of the direct anti-ischemic effect of the drug in both type 1 diabetes mellitus and T2DM. In our study, myocardial tolerance to ischemia in rats with neonatal streptozotocin T2DM was investigated using the model of global ischemia-reperfusion of the isolated perfused heart. Metformin was administered i.p. at a dose of 200 mg/kg/day for 3 days prior to isolated heart perfusion. The results showed that both the infarct size and postischemic recovery of left ventricular function were not different between controls and metformin-treated animals. At the same time, the infarct size in the T2DM animals was significantly lower than that in the controls (24.4 ± 7.6% versus 45.0 ± 10.4%, resp., P < .01), indicative of the metabolic preconditioning in T2DM. It follows that the protocol of metformin administration used in this study had not elicited cardioprotective effect in animals with T2DM so that the different mechanism(s) may underlie the beneficial effect of metformin on cardiovascular complications in patients with T2DM which, however, would need further investigation

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