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Mitochondrial respiration of brown adipose tissue in development of cold acclimation
Galatík, František ; Žurmanová, Jitka (advisor) ; Holzerová, Kristýna (referee)
Historical experiments regarding the influence of low ambient temperatures were often accompanied with the development of detrimental effects. Our laboratory recently published a protocol of mild cold acclimation (5 weeks in 8 ± 1 řC) which induces cardioprotective phenotype in rats (Rattus norvegicus). An important mechanism of cold acclimation is the activation and increase of brown adipose tissue. Besides the nonshivering thermogenesis brown adipose tissue can produce a multitude of autocrine, paracrine, and endocrine factors which might positively influence whole-body metabolism and function of other important organs. The effect of cold acclimation on brown adipose tissue is not however explored very well. The aim of this work was to asses selected parameters of respiration of isolated brown adipose tissue mitochondria of control rats living in 24 ± 1 řC and compare it with that of rats exposed to 8 ± 1 řC for 1 day, 3 days, 10 days, and 5 weeks. Results of this works were 1) the increase in respiration occurs after the 1-day cold exposure and 2) the highest respiration per 1 mg of mitochondrial protein appears to be after the 10 days of cold exposure. Key-words: Brown adipose tissue, mitochondria, respiration, cold acclimation
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Transcriptional regulation in the development of the cardiac sympathetic system
Matějková, Kateřina ; Pavlínková, Gabriela (advisor) ; Holzerová, Kristýna (referee)
To improve modern therapeutic and diagnostic methods, it is crucial to understand the development of the cardiac sympathetic system and to identify the genes involved in its regulation. Neural crest cells give rise to the sympathetic precursors that migrate towards the dorsal aorta. This migration is regulated by the NRP1/SEMA3A and neuregulin/ERBB signaling. The differentiation towards the sympathetic phenotype is regulated by transcriptional factor networks, including ASCL1, PHOX2A/B, GATA3, HAND2, HIF1A and ISL1. Next, neurons migrate to the final paravertebral position, which is regulated by the BDNF/TRKB signaling. The final step in the development of cardiac sympathetic neurons is the axon growth and guidance towards the heart. This is regulated by the NGF/TRKA and NRP1/SEMA3A signaling. This thesis aims to map current knowledge of different regulation pathways involved in the cardiac sympathetic development (especially in the mouse model) with emphasis on transcriptional factors. This type of information should help us better understand the pathophysiology of some cardiovascular diseases associated with the dysfunctional sympathetic system, such as arrhythmias, congestive heart failure or myocardial infarction, which remain to be main causes of death worldwide.
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The effect of season on mitochondrial swelling of rat heart after cold acclimation
Kašík, Petr ; Horníková, Daniela (advisor) ; Holzerová, Kristýna (referee)
Risk of death from cardiovascular disease is substantially increased throughout winter season and by exposure of organism to acute cold stress. However, several studies have suggested that some cold acclimation models could act cardioprotectively. The thesis is focused on effects of acute and chronic cold acclimation on swelling of rat heart mitochondria. Mitochondrial swelling is, besides other things, caused by massive influx of Ca2+ into the mitochondria especially during ischemia-reperfusion injury. By that, mitochondria permeability transition pore is being opened and subsequently, this could end up in mitochondrial burst and cell death, eventually. Lower rate of mitochondrial swelling indicates greater mitochondrial resistance. The results express higher mitochondrial resistance after acute cold exposure and chronic cold acclimation. Key words: cold, mitochondria, Ca2+ ions, swelling, MPTP, myocardium, ROS, ischemia
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Fibroblast growing factor 21 and its function
Vrabcová, Veronika ; Žurmanová, Jitka (advisor) ; Holzerová, Kristýna (referee)
Fibroblast growth factor (FGF21) is a hormone produced predominantly in the liver and it is essential for many biological processes in the human body. FGF21 can dramatically affect an individual's development similarly to other members of the FGF family. In recent years, increasing attention has been paid, especially for its potential use in the clinical practice, for example, this hormone could serve as a biomarker of mitochondrial respiratory chain disorders, increase insulin sensitivity and reduce fat in obese individuals. We are interested in its cytoprotective action increasing resistance of the heart to ischemia-reperfusion injury. FGF21 is also released from other organs in a smaller amount under certain conditions such as during starvation and exercise, or in response to hypertrophic signals in the heart. The aim of this work is to summarize the broad action of FGF21 in the body with a focus on its function in the heart. Key words: Fibroblast growth factor 21, metabolism, muscle, heart
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The role of adrenergic signalling and mitochondria in cardioprotection
Macíčková, Eliška ; Žurmanová, Jitka (advisor) ; Holzerová, Kristýna (referee)
Cardiovascular diseases such as myocardial infarction or heart failure are one of the main causes of death in today's developed world. These diseases are accompanied by pathophysiological changes in the cell, which are very often associated with changes in adrenergic receptor signalling and mitochondrial function. Therefore, these functional units have been intensively studied in an attempt to discover the effective treatment. Currently, endogenous protective mechanisms are known to increase the resistance of heart to the pathophysiological states, and some of the mechanism targets directly into the mitochondria. In particular, the reduction in excessive production of reactive oxygen species and the decrease in sensitivity of mitochondrial permeability transition pore opening has been repeatedly described. Many of the contributing signalling pathways are related to adrenergic receptors. Thus, the aim of the present work is to link knowledge about the role of adrenergic signalling in cardioprotective mechanisms directed to mitochondria. Key words: heart, adrenergic signalization, mitochondria, cardioprotection
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The role of the m6A pathway in the regulation of brain ontogenesis in the rat
Tabáková, Petra ; Telenský, Petr (advisor) ; Holzerová, Kristýna (referee)
N6-methyladenosine (m6A) is the most ubiquitous post-transcriptional RNA modification and has an important role in determining the fate of mRNA transcripts. Among the key proteins of the m6A pathway are methyltransferases (METTL family enzymes), demethylases (FTO, ALKBH family enzymes), and m6A binding proteins (e.g., YTHDF family) which recognize RNA sequences depending on the amount and localization of m6A in target transcripts and subsequently influence the fate of mRNA transcripts. The role of methyltransferases and demethylases is to provide a dynamic balance of m6A levels and possibly to convey mechanisms of specificity for these so-called epitranscriptomic marks, which are not yet fully understood. The main objective of this work was to determine the relative changes in the expression of key m6A pathway proteins during early postnatal development and adulthood in the rat brain. We found that the level of expression of key m6A pathway proteins decreases from birth to adulthood, with the exception of a transient increase between postnatal days 10 and 18. During this period, we also found significant changes in the expression of respiratory chain complexes. However, further research is needed to provide evidence of a mechanistic link between the m6A pathway and brain energy homeostasis during...
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The role of GPCRs and their signalling systems in cardioprotection
Svobodová, Ivana ; Novotný, Jiří (advisor) ; Holzerová, Kristýna (referee)
G protein-coupled receptors (GPCRs) are a family of membrane receptors with hundreds of members, many of them present in the heart, where their signalling systems are involved in regulation of many cellular processes. An important role of GPCRs is the cardioprotection against cardiac ischemia-reperfusion injury, which mainly involves the so-called RISK pathway containing of kinases signalling for cell survival and against apoptosis. By protecting the heart during ischemia/reperfusion they can prevent irreversible cardiac injury, including myocardial infarction or cardiac dysfunctions, which can lead to heart failure. GPCRs regulate many processes linked to pathophysiology of heart failure - hypertrophy, fibrosis, loss of cardiac function. Understanding the role of individual receptors in these cardioprotective and cardiotoxic processes is essential for the development of new drugs.
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The role of Arachidonic acid metabolites in cardiovascular system and signaling of heart failure
Liptáková, Andrea ; Žurmanová, Jitka (advisor) ; Holzerová, Kristýna (referee)
Arachidonic acid (AA) is polyunsaturated acid that plays an important role in regulation of physiology, bioenergetic and signalling cascades in the heart. AA released by phospholipase A2-catalysed hydrolysis of membrane phospholipids serves as substrate for cyclooxygenase, lipooxygenase and cytochrome P450 epoxygenase to produce a wide spectrum of lipid second messengers, eicosanoids. These very biologically potent molecules regulate a number of cellular processes in the cardiovascular system and changes in their composition and concentration significantly contribute to heart failure. The aim of this thesis was to summarize current knowledge about the role of AA in failing heart. Keywords : Heart, Arachidonic Acid, Heart Failure, Eicosanoids, Cardiovascular System
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The role of protein kinase C and its targets in cardioprotection
Holzerová, Kristýna ; Hlaváčková, Markéta (advisor) ; Alán, Lukáš (referee) ; Vízek, Martin (referee)
The mortality of cardiovascular diseases remains high and it likely tends to increase in the future. Although many ways how to increase the resistance against myocardial ischemia- reperfusion damage have been described, few of them were transferred into clinical practice. Cardioprotective effect of chronic hypoxia has been described during 60s of the last century. Its detailed mechanism has not been elucidated, but a number of components has been identified. One of these components presents protein kinase C (PKC). The role of PKC was described in detail in the mechanism of ischemic preconditioning, but its involvement in the mechanism of cardioprotection induced by chronic hypoxia remains unclear. One reason is the amount of PKC isoforms, which have often contradictory effects, and the diversity of hypoxic models used. The most frequently mentioned isoforms in connection with cardioprotection are PKCδ and PKCε. The aim of my thesis was to analyze changes in these PKC isoforms at two different cardioprotective models of hypoxia - intermittent hypobaric (IHH) and continuous normobaric hypoxia (CNH). We also examined the target proteins of PKCδ and PKCε after the adaptation to IHH, which could be involved in the mechanism of cardioprotection. These included proteins associated with apoptosis and...
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The role of pro- and anti-inflammatory factors in adaptation of heart to hypoxia
Benák, Daniel ; Hlaváčková, Markéta (advisor) ; Holzerová, Kristýna (referee)
Myocardial hypoxia induces several physiological changes on cellular and molecular level in order to keep homeostasis in low oxygen conditions. Essential role in this adaptive response is played by secretory regulatory proteins called cytokines. Differences in concentrations of pro-inflammatory and anti-inflammatory cytokines during hypoxic conditions in the myocardium may significantly influence the fate of the heart tissue, i.e. contribute to its injury or protection. This knowledge is used in experimental cardioprotective strategies - adaptation to chronic hypoxia, ischemic preconditioning, postconditioning and remote conditioning - all of which affect the cytokine levels. The main pro-inflammatory cytokines are TNF-α, IL-1 and cytokine family IL-6. The principal anti-inflammatory cytokine is IL-10. This thesis aims to summarize the effects of pro- and anti-inflammatory cytokines in adaptation of heart to hypoxia and to cover their pathological and protective impact on the myocardium.
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