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Effect of erythropoietin on myocardial ischemic tolerance
Jindrová, Helena ; Kolář, František (advisor) ; Žurmanová, Jitka (referee)
Adaptation to chronic hypoxia increases myocardial resistance to acute ischemia/reperfusion (I/R) injury, similarly to application of exogenous erythropoietin (EPO). Nevertheless, it is not known if EPO induced by chronic hypoxia plays a role in its cardioprotective mechanism. The aim of this study was to find out if protective effect of exogenous EPO adds up to protection offered by chronic hypoxia. Adult male mice (ICR) were adapted to intermittent hypobaric hypoxia 8 hours per day, 5 days per week for 5 weeks. The degree of hypoxia corresponded to 7000 metres. Control animals were housed for the same time in normoxic environment. Resistance to I/R injury was assessed according to size of myocardial infarction induced by 45-min global ischemia and 1-h reperfusion of the heart in vitro. Animals were treated 24 h before the experiment with 200 or 5000 U/kg EPO. Treatment with 200 U/kg EPO was sufficient to significantly limit infarct size in normoxic animals (33,56 ± 2,93 % vs. 25,71 ± 2,29 %). Hypoxic adaptation decreased infarct area to 23,49 ± 2,30%, but additive effect of EPO in hypoxic group was not detected. The results indicate that exogenous EPO employs the same cardioprotective mechanisms as adaptation to chronic intermittent hypoxia. Preliminary results indicate that repeated application of EPO...
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Echocardiographic assessment of left ventricular systolic function in rats adapted to hypoxia and exercise training
Hrdlička, Jaroslav ; Papoušek, František (advisor) ; Vybíral, Stanislav (referee)
- 4 - Abstract Adaptation to hypoxia or exercise training has cardioprotective effects against acute ischemic injury, but can potentially negatively influence heart function. Possible negative changes depend on the degree of hypoxia and exercise training intensity. It is therefore necessary to evaluate the effects of the specific adaptation protocols used. The ideal technique is echocardiography, which enables non-invasive, repeated and long-term measurements of the same individual allowing to study the development of changes in the course of adaptation. The aim of this study was to determine the effects of selected protocols of adaptation to intermittent hypobaric hypoxia (corresponding to the altitude of 4,000 to 8,000 meters above sea level, for 15 weeks in total) and exercise training (running speed 30 m.min-1 for 60 min a day, 4 weeks in total) on the left ventricle geometry and systolic function in rats. We assessed basic echocardiographic parameters of the ventricle geometry and function such as fractional shortening, ejection fraction, stroke volume, cardiac output etc. The adaptation of rats to intermittent hypobaric hypoxia lead neither to the impairment of systolic function nor to the development of left ventricle hypertrophy compared to controls; signs of moderate hypertrophy were observed only...
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Myocardial beta-adrenergic signaling during adaptation of rats to chronic hypoxia
Hahnová, Klára ; Novotný, Jiří (advisor) ; Ostašov, Pavel (referee)
Endogenous cardiac protection against acute ischemia/reperfusion injury can by increased by cardiac adaptation to various forms of chronic hypoxia. Chronic hypoxia induces a large variety of adaptive changes in the myocardium that could be considered as protective, but the exact mechanism of increased ischemic tolerance is unknown. Different studies suggest that catecholamine release and their effect on -adrenergic signaling after adaptation to chronic hypoxia contributes to cardioprotection. In this study we focused on characterization of -adrenergic receptors ( -ARs) in the myocardium of rats after adaptation to three different hypoxic conditions: 1. intermittent normobaric hypoxia - INH/R (23 h hypoxia, 1 h reoxygenation), 2. intermittent normobaric hypoxia - INH (8 h hypoxia, 16 h normoxia), 3. continuous normobaric hypoxia - CNH (24 h hypoxia). We compared how each hypoxic model affects the total number of -adrenergic receptors and proportion of individual subtypes ( 1-and 2-ARs) in the left and right ventricles compared control normoxic rats. The INH model had apparently no effect on -ARs in either ventricles. On the other hand, adaptation to INH/R and CNH was accompanied by a significant decrease (by about 25%) in the total number of -adrenergic receptors in the right ventricles. Our present...
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Mitochondrial subpopulations in rat myocardium - effect of chronic hypoxia
Kovalčíková, Jana ; Nováková, Olga (advisor) ; Žurmanová, Jitka (referee)
Adaptation to chronic hypoxia induces endogenous cardioprotection and increases the heart resistance to ischemia/reperfusion injury. The heart mitochondria, which produce reactive oxygen species (ROS) in addition to ATP, play an important role in these processes. During ischemia/reperfusion, ROS are produced in excessive amounts and damage the cells. However, in lower concentrations, ROS are involved in the signalling pathway of cardioprotection induced by adaptation to chronic hypoxia. In the heart, two mitochondrial subpopulations have been observed, subsarcolemmal mitochondria (SSM) and intermyofibrillar mitochondria (IMFM), which differ in cell localization as well as in morphological and biochemical properties. The aim of this work was to introduce the method of SSM and IMFM isolation in our laboratory and to analyse their antioxidative capacity after adaptation to chronic hypoxia. Adult male Wistar rats were kept either under normoxic conditions or exposed to intermittent high-altitude hypoxia (IHA; 7000 m, 5 days a week/8 hours a day, totally 25 exposures). Mitochondrial subpopulations were isolated from heart left ventricle and their functionality was verified by measuring oxygen consumption and enzyme activities. The IMFM had higher oxygen consumption in comparison with SSM and activities...
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Role of protein kinase C isoforms in cardioprotective mechanism of chronic hypoxia
Hlaváčková, Markéta ; Novák, František (advisor) ; Kopecký, Jan (referee) ; Novotný, Jiří (referee)
Cardiovascular diseases, particularly acute myocardial infarction, are one of the leading causes of death in developed countries. It is well known that adaptation to chronic intermittent hypobaric hypoxia (IHH) confers long-lasting cardiac protection against acute ischemia/reperfusion injury. Protein kinase C (PKC) appears to play a role in its cardioprotective mechanism since the administration of general PKC inhibitor completely abolished the improvement of ischemic tolerance in IHH hearts. However, the involvement of individual PKC isoforms remains unclear. Therefore, the primary aim of this study was to investigate the potential involvement of PKCδ and PKCε, the most prevalent PKC isoforms in rat heart, in the mechanism of IHH-induced cardioprotection. We showed that IHH up- regulated PKCδ protein in left ventricle, enhanced its phosphorylation on Ser643 and increased its co-localization with markers of mitochondrial and sarcolemmal membranes. PKCδ subcellular redistribution induced by IHH as well as the infarct size-limiting effect of IHH was reversed by acute treatment with PKCδ inhibitor rottlerin. These data support the view that PKCδ plays a significant role in IHH-induced cardioprotection. On the other hand, adaptation to IHH decreased the PKCε total protein level without affecting its...
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The role of mitochondria in cardioprotective effect induced by hypoxia in rat
Lomnický, Matouš ; Žurmanová, Jitka (advisor) ; Hlaváčková, Markéta (referee)
Aerobic organisms need sufficient oxygen supply to maintain homeostasis. These organisms are frequently exposed in hypoxic environments naturally, and also occur in hypoxic states in various pathological conditions. Cardioprotective effect of hypoxia had been recognised more than 30 years ago; and later on, cardioprotective effects of ischemic preconditioning were discovered. Long term exposure to hypobaric hypoxia activates cardioprotective mechanisms, which lower the aftermathes of short term ischemia of myocardia and the effects of further health complications. The core of protective mechanisms has not yet been fully clarified. This work deals with the significance of mitochondria on cardioprotection during hypobaric hypoxia adaptation. This work describes physiological adaptive processes on selected animals on natural hypoxic conditions and also molecular mechanisms, examined on experimental models. Molecular mechanisms of the origins of cardioprotective effects discovered so far, mainly indicate PKC signal pathways through thyrosine kinase and mitogenes of activated kinase and also indicate an activation of sarcKATP-channels and mitoKATP-channels. Opening of these channels can protect mitochondria against a Ca2+ overload, or can lead to an increase in mitochondrial capacity which is possibly connected...
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Autophagy in the heart
Šprláková, Katarína ; Hlaváčková, Markéta (advisor) ; Tomšů, Eva (referee)
Currently, it is growing evidence that autophagy is involved in the prevention of various diseases, which of course also includes heart diseases. This thesis is therefore aimed at clarifying the role of autophagy in the heart, especially during ischemia and subsequent reperfusion. Autophagy is a physiological cellular process by which the cell maintains homeostasis by eliminating long-lived proteins and damaged organelles. The role of autophagy during ischemia/reperfusion in the heart is complex. Predominantly it functions as a pro-survival pathway, because it protects the heart from ischemia or hypoxia. However, when triggered over, which happens during reperfusion, it may lead to cell death. In the heart autophagy is activated in response to various stimuli, such as decrease in ATP and subsequent activation of AMPK, protein Bnip3, reactive oxygen and nitrogen species, the opening of mitochondrial permeability transition pore, endoplasmic reticulum stress or unfolded protein response.
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Mitochondrial dynamics in myocardium.
Weissová, Romana ; Nováková, Olga (advisor) ; Kalous, Martin (referee)
The heart is an absolutely vital body organ, which requires sufficient amount of active mitochondria for its energy demanding activity. The functionality of a mitochondrial population is maintained through mitochondrial turnover, encompassing mitophagy removing damaged mitochondria and mitochondrial biogenesis responsible for the emergence of new organelles. Dynamic processes of mitochondrial fusion and fission can also contribute to the maintenance of a healthy mitochondrial population. Mitochondrial fusion and fission have not yet been proven in cardiomyocytes, although these cells possess all the proteins required for these events. These processes, however, take on the importance during pathological conditions, when changes in the amount of protein applied in the mitochondrial dynamics occur. The modification in mitochondrial phenotype leads to the cell damage. Understanding the role of mitochondrial dynamics in myocardium may contribute to the development of new heart diseases treatments.
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Analysis of selected gene transcripts in the rat myocardium adaptated to chronic hypoxia
Kašparová, Dita ; Žurmanová, Jitka (advisor) ; Nováková, Olga (referee)
Dita Kašparová Chronická hypoxie a exprese genů 4 Abstract Adaptation to chronic hypoxia (CH) is characterized by a variety of functional changes in order to maintain metabolic and energy homeostasis. It has been known for many years that both humans and animals indigenous or adapted to high-altitude hypoxia are more tolerant to an acute ischemic injury of the heart. Cardioprotective mechanisms activated by adaptive responses to chronic hypoxia can be the result of altered transcriptional regulations in left ventricles. Here we report results from the gene expression profiling of adaptive responses in three models of chronically hypoxic heart. Adult male Wistar rats were exposed for 21 days to either continuous normobaric hypoxia (CCH; 10% O2) or CCH interrupted daily by 1-hour reoxygenation (RCH) or CCH interrupted daily by 16-hour (CIH). Cardiprotective effect of CCH adaptation is abolished by brief daily reoxygenation, RCH adaptation. In the present study, we aimed to determine myocardial mRNA expression of 19 candidate genes divided into three important groups: i) Hypoxia inducible factor (HIF1α) and its prolyl and asparaginyl hyroxylases (PHDs and FIH respectively, ii) Creatine kinase (CK) isoenzymes which play important role in energy homeostases of heart and iii) the group of main enzymatic...
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The role of lipids and ROS in cardioprotective mechanism of chronic hypoxia
Balková, Patricie ; Nováková, Olga (advisor) ; Drahota, Zdeněk (referee) ; Šmíd, František (referee)
The role of lipids and ROS in cardioprotective mechanism of chronic hypoxia Cardiovascular diseases, mainly ischemic heart disease is one of the most frequently cause of morbidity and mortality in developed countries. Therefore effective protection of the heart against ischemia and reperfusion injury is the crucial aim of experimental and clinical cardiology. One of the main streams of cardiovascular research is looking for possibilities of natural heart resistance augmentation. Adaptation to chronic hypoxia is one possibility how to protect the heart against ischemia-reperfusion injury. Chronic hypoxia increases resistance of the myocardium to acute deficiency of oxygen leading to vetricular arrythmias, postischemic contractile dysfunction and necrotic changes in the tissue. Recently, it has been shown that reactive oxygen species (ROS) play an important role in the cardioprotective mechanism of chronic hypoxia. It is known that oxidative stress has a harmful effect in acute ischemia-reperfusion however ROS generated during the adaptation to hypobaric intermittent chronic hypoxia play a role in the induction of cardioprotection. In this study, we demonstrated that adaptation of adult rats to chronic hypoxia increased the activity and protein abundance of manganese superoxide dismutase (MnSOD) in the...
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