The aim of this study was to measure expression levels of microRNAs (miRNAs) (miRNA-1, -15b and -21) in the rat myocardium after a single dose of ionizing radiation (6-7 Gy/min, total 25 Gy). The rats were treated with selected drugs (Atorvastatin, acetylsalicylic acid (ASA), Tadalafil, Enbrel) for six weeks after irradiation. MiRNAs levels were measured by RT-qPCR. Irradiation down-regulated miRNA-1 in irradiated hearts. In Tadalafil- and Atorvastatin-treated groups, miRNA-1 expression levels were further decreased compared with irradiated controls. However, Enbrel increased miRNA-1 level in irradiated hearts similarly to that in non-irradiated untreated group. Increase of miRNA-15b is pro-apoptotic in relationship with ischemia. Irradiation caused down-regulation of miRNA-15b. Administration of ASA in the irradiated group resulted in the increase of miRNA-15b expression compared to non-treated controls without irradiation. After Enbrel administration, miRNA-15b levels were overexpressed compared to non-treated normal group. MiRNA-21 belongs to the most markedly up-regulated miRNAs in response to cardiogenic stress. MiRNA-21 was increased nearly 2-fold compared to non-treated hearts whereas Tadalafil reduced miRNA-21 levels (about 40 %). Our study suggests that Enbrel and Tadalafil changed miRNAs expression values of the irradiated rats to the values of nonirradiated controls, thus they might be helpful in mitigation of radiation-induced toxicity., B. Kura, C. Yin, K. Frimmel, J. Krizak, L. Okruhlicova, R. C. Kukreja, J. Slezak., and Obsahuje bibliografii
We aimed to determine the impact of Ca2+-related disorders induced in intact animal hearts on ultrastructure of the cardiomyocytes prior to occurrence of severe arrhythmias. Three types of acute experiments were performed that are known to be accompanied by disturbances in Ca2+ handling. Langedorffperfused rat or guinea pig hearts subjected to K+-deficient perfusion to induce ventricular fibrillation (VF), burst atrial pacing to induce atrial fibrillation (AF) and open chest pig heart exposed to intramyocardial noradrenaline infusion to induce ventricular tachycardia (VT). Tissue samples for electron microscopic examination were taken during basal condition, prior and during occurrence of malignant arrhythmias. Cardiomyocyte alterations preceding occurrence of arrhythmias consisted of non-uniform sarcomere shortening, disruption of myofilaments and injury of mitochondria that most likely reflected cytosolic Ca2+ disturbances and Ca2+ overload. These disorders were linked with non-uniform pattern of neighboring cardiomyocytes and dissociation of adhesive junctions suggesting defects in cardiac cell-to-cell coupling. Our findings identified heterogeneously distributed high [Ca2+]i-induced subcellular injury of the cardiomyocytes and their junctions as a common feature prior occurrence of VT, VF or AF. In conclusion, there is a link between Ca2+-related disorders in contractility and coupling of the cardiomyocytes pointing out a novel paradigm implicated in development of severe arrhythmias., N. Tribulova, V. Knezl, B. Szeiffova Bacova, T. Egan Benova, C. Viczenczova, E. Gonçalvesova, J. Slezak., and Obsahuje bibliografii
Direct cell-to-cell communication in the heart is maintained via gap junction channels composed of proteins termed connexins. Connexin channels ensure molecular and electrical signals propagation and hence are crucial in myocardial synchronization and heart function. Disease-induced gap junctions remodeling and/or an impairment or even block of intercellular communication due to acute pathological conditions results in derangements of myocardial conduction and synchronization. This is critical in the development of both ventricular fibrillation, which is a major cause of sudden cardiac death and persistent atrial fibrillation, most common arrhythmia in clinical practice often resulting in stroke. Many studies suggest that alterations in topology (remodeling), expression, phosphorylation and particularly function of connexin channels due to age or disease are implicated in the development of these life-threatening arrhythmias. It seems therefore challenging to examine whether compounds that could prevent or attenuate gap junctions remodeling and connex in channels dysfunction can protect the heart against arrhythmias that cause sudden death in humans. This assumption is supported by very recent findings showing that an increase of gap junctional conductance by specific peptides can prevents atrial conduction slowing or re-entrant ventricular tachycardia in ischemic heart. Suppression of ischemia-induced dephosphorylation of connexin seems to be one of the mechanisms involved. Another approach for identifying novel treatments is based on the hypothesis that even non-antiarrhythmic drugs with antiarrhythmic ability can modulate gap junctional communication and hence attenuate arrhythmogenic substrates., N. Tribulová, V. Knezl, Ľ. Okruhlicová, J. Slezák., and Obsahuje bibliografii a bibliografické odkazy
Omega-3 fatty acids (Ω3FA) are known to reduce hypertriglyceridemia- and inflammation-induced vascular wall diseases. However, mechanisms of their effects are not completely clear. We examined, whether 10-day Ω3FA diet can reduce bacterial lipopolysaccharide-induced changes in expression of gap junction protein connexin40 (Cx40) in the aorta of hereditary hypertriglyceridemic (hHTG) rats. After administration of a single dose of lipopolysaccharide (LPS, 1 mg/kg, i.p.) to adult hHTG rats, animals were fed with Ω3FA diet (30 mg/kg/day) for 10 days. LPS decreased Cx40 expression that was associated with reduced acetylcholine-induced relaxation of aorta. Ω3FA administration to LPS rats had partial anti-inflammatory effects, associated with increased Cx40 expression and improved endothelium dependent relaxation of the aorta. Our results suggest that 10-day Ω3FA diet could protect endothelium-dependent relaxation of the aorta of hHTG rats against LPS-induced damage through the modulation of endothelial Cx40 expression, K. Frimmel, R. Sotníková, J. Navarová, I. Bernátová, J. Križák, Z. Haviarová, B. Kura, J. Slezák, Ľ. Okruhlicová., and Obsahuje bibliografii
Excessive production of oxygen free radicals has been regarded as a causative common denominator of many pathological processes in the animal kingdom. Hydroxyl and nitrosyl radicals represent the major cause of the destruction of biomolecules either by a direct reaction or by triggering a chain reaction of free radicals. Scavenging of free radicals may act preventively or therapeutically. A number of substances that preferentially react with free radicals can serve as scavengers, thus increasing the internal capacity/activity of endogenous antioxidants and protecting cells and tissues against oxidative damage. Molecular hydrogen (H2) reacts with strong oxidants, such as hydroxyl and nitrosyl radicals, in the cells, that enables utilization of its potential for preventive and therapeutic applications. H2 rapidly diffuses into tissues and cells without affecting metabolic redox reactions and signaling reactive species. H2 reduces oxidative stress also by regulating gene expression, and functions as an anti-inflammatory and anti-apoptotic agent. There is a growing body of evidence based on the results of animal experiments and clinical observations that H2 may represent an effective antioxidant for the prevention of oxidative stress-related diseases. Application of molecular hydrogen in situations with excessive production of free radicals, in particular, hydroxyl and nitrosyl radicals is relatively simple and effective, therefore, it deserves special attention., J. Slezák, B. Kura, K. Frimmel, M. Zálešák, T. Ravingerová, C. Viczenczová, Ľ. Okruhlicová, N. Tribulová., and Obsahuje bibliografii
Remote ischemic preconditioning (RIPC) is a novel strategy of protection against ischemia-reperfusion (IR) injury in the heart (and/or other organs) by brief episodes of non-lethal IR in a distant organ/tissue. Importantly, RIPC can be induced noninvasively by limitation of blood flow in the extremity implying the applicability of this method in clinical situations. RIPC (and its delayed phase) is a form of relatively short-term adaptation to ischemia, similar to ischemic PC, and likely they both share triggering mechanisms, whereas mediators and end-effectors may differ. It is hypothesized that communication between the signals triggered in the remote organs and protection in the target organ may be mediated through substances released from the preconditioned organ and transported via the circulation (humoral pathways), by neural pathways and/or via systemic anti-inflammatory and antiapoptotic response to short ischemic bouts. Identification of molecules involved in RIPC cascades may have therapeutic and diagnostic implications in the management of myocardial ischemia. Elucidation of the mechanisms of endogenous cardioprotection triggered in the remote organ could lead to the development of diverse pharmacological RIPC mimetics. In the present article, the authors provide a short overview of RIPC-induced protection, proposed underlying mechanisms and factors modulating RIPC as a promising cardioprotective strategy., T. Ravingerova, V. Farkasova, L. Griecsova, S. Carnicka, M. Murarikova, E. Barlaka, F. Kolar, M. Bartekova, L. Lonek, J. Slezak, A. Lazou., and Obsahuje bibliografii
Thyroid hormones (TH) are powerful modulators of heart function, but their arrhythmogenic effects are less elucidated. We have examined both acute and long-term action of TH on the heart susceptibility to the ventricular fibrillation (VF) and on the heart ability to terminate VF and restore a sinus rhythm. Triiodothyronine (T3) was applied in the range of 10-9-10-6 mol/l in acute experiments using isolated perfused aged (14-month-old) guinea pig hearts. L-thyroxine (T4) was applied in the dose of 50 μg/100g/day to young (3-month-old) and aged (20-month-old) rats for 2 weeks. The T4 treatment resulted in an increased susceptibility of young, but not adult rat hearts to a hypokalemia induced VF and facilitated a spontaneous sinus rhythm (SSR) restoration in the latter group. The acute T3 administration in the range of 10-9-10-7 mol/l significantly decreased the susceptibility of an isolated heart to an electrically induced VF and also facilitated the sinus rhythm restoration. The SSR restoration was, however, not affected by 10-6 mol/l concentration of T3, which also led to an increased VF susceptibility. Results indicate that TH can affect the susceptibility of the heart to VF and its ability to restore the sinus rhythm via acute (non-genomic) and long-term (genomic) actions. Furthermore, an anti- and pro-arrhythmic potential of TH appears to be age- and dose-dependent., V. Knezl, T. Soukup, Ľ. Okruhlicová, J. Slezák, N. Tribulová., and Obsahuje bibliografii a bibliografické odkazy