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The role of uncoupling proteins (UCP) in cardioprotection
Furmánková, Tereza ; Horníková, Daniela (advisor) ; Adamcová, Kateřina (referee)
Cardiovascular disease (CVD) is the world's leading cause of death. Almost 18 million people die of CVD each year, and the prevalence continues to rise for both men and women. It is now clear that the maintenance of mitochondrial membrane potential can play an important role in the pathophysiology of the heart and it is involved in cardioprotective mechanisms. Mitochondrial membrane potential can be affected in a various of ways, one of them is the stimulation of uncoupling proteins. An elaboration of previous findings in this work has shown that uncoupling proteins have the effect of reducing oxygen radicals, inhibiting apoptosis, affect the production of ATP and atherosclerotic plaques and protect the heart from lipid toxicity. There are several ways to regulate their gene expression, and influencing these pathways may be a way to achieve cardioprotection. Key words: uncoupling proteins, mitochondria, cardioprtoection, thyroid hormones, fatty acids, adipose tissue, reactive oxygen species, FGF21
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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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Role of phospholipases A2 in the mechanism of cardioprotection induced by adaptation to chronic hypoxia
Míčová, Petra
Cardiovascular diseases, particularly acute myocardial infarction, are the leading causes of death in developed countries including the Czech Republic. One of the ways to increase cardiac resistance against acute ischemia/reperfusion (I/R) injury is adaptation to chronic hypoxia. However, changes at the molecular level associated with this adaptation have still not been fully explored. It is obvious that the myocardial function depends on maintaining membrane integrity and cellular homeostasis of cardiomyocytes. From this perspective, phospholipases A2 (PLA2) are the key enzymes that take part in the remodeling and repairing of the cell membranes. Moreover, PLA2 are also involved in generation of lipid signaling molecules - free long chain fatty acids (FA) and 2-lysophopholipids. In myocardium, members of three major PLA2 classes are present: cytosolic PLA2 (cPLA2), calcium-independent PLA2 (iPLA2) and secretoric PLA2 (sPLA2). This thesis aimed to determine the following in the left ventricular myocardium of adult male Wistar rats: 1) The effect of intermittent hypobaric hypoxia (IHH; 8 hours/day, 5 days/week, 5 weeks, ~ 7000 m) on the expression of total cPLA2α and its phosphorylated form (p-cPLA2α, Ser505 ), and further iPLA2 and sPLA2IIA, as well as signaling proteins activating cPLA2α enzyme...
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Role of protein kinase C isoforms in cardioprotective mechanism of chronic hypoxia
Hlaváčková, Markéta
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 PKC 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 PKC total protein level without affecting its...
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Role of phospholipases A2 in the mechanism of cardioprotection induced by adaptation to chronic hypoxia
Míčová, Petra ; Novotný, Jiří (advisor) ; Kuda, Ondřej (referee) ; Kazdová, Ludmila (referee)
Cardiovascular diseases, particularly acute myocardial infarction, are the leading causes of death in developed countries including the Czech Republic. One of the ways to increase cardiac resistance against acute ischemia/reperfusion (I/R) injury is adaptation to chronic hypoxia. However, changes at the molecular level associated with this adaptation have still not been fully explored. It is obvious that the myocardial function depends on maintaining membrane integrity and cellular homeostasis of cardiomyocytes. From this perspective, phospholipases A2 (PLA2) are the key enzymes that take part in the remodeling and repairing of the cell membranes. Moreover, PLA2 are also involved in generation of lipid signaling molecules - free long chain fatty acids (FA) and 2-lysophopholipids. In myocardium, members of three major PLA2 classes are present: cytosolic PLA2 (cPLA2), calcium-independent PLA2 (iPLA2) and secretoric PLA2 (sPLA2). This thesis aimed to determine the following in the left ventricular myocardium of adult male Wistar rats: 1) The effect of intermittent hypobaric hypoxia (IHH; 8 hours/day, 5 days/week, 5 weeks, ~ 7000 m) on the expression of total cPLA2α and its phosphorylated form (p-cPLA2α, Ser505 ), and further iPLA2 and sPLA2IIA, as well as signaling proteins activating cPLA2α enzyme...
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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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Myocardial tolerance to ischemia/reperfusion injury - possible protective mechanisms
Alánová, Petra ; Neckář, Jan (advisor) ; Nováková, Olga (referee) ; Vaněčková, Ivana (referee)
Ischemic heart disease is the leading cause of death and disability worldwide. The effects of ischemic heart disease are usually attributable to the detrimental effects of acute myocardial ischemia/reperfusion (I/R) injury. The aim of the thesis was to contribute to current effort to clarify the basis of mechanisms that could save the heart from I/R injury. The whole thesis is based on four studies; while the first three are published, the fourth one has been under revision. In the first study, we proved the involvement of nitric oxide (NO) in the cardioprotective mechanism of chronic hypoxia (CH). We described that exogenously increased availability of NO as well as inhibition of phosphodiesterase type 5 led to increased myocardial tolerance of normoxic and chronically hypoxic rats. The effects of both interventions were not additive, suggesting that NO is included in cardioprotective signaling of CH. Second study continued in investigating molecular mechanisms underlying cardioprotection induced by CH. We showed that infarct size-limiting effect of adaptation to CH was accompanied by increased myocardial concentration of tumor-necrosis factor alpha (TNF-α) and TNF-α receptor R2. In the third study, we examined the effect of dexrazoxane (DEX), the only clinically approved drug against...
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Myocardial tolerance to ischemia/reperfusion injury - possible protective mechanisms
Alánová, Petra
Ischemic heart disease is the leading cause of death and disability worldwide. The effects of ischemic heart disease are usually attributable to the detrimental effects of acute myocardial ischemia/reperfusion (I/R) injury. The aim of the thesis was to contribute to current effort to clarify the basis of mechanisms that could save the heart from I/R injury. The whole thesis is based on four studies; while the first three are published, the fourth one has been under revision. In the first study, we proved the involvement of nitric oxide (NO) in the cardioprotective mechanism of chronic hypoxia (CH). We described that exogenously increased availability of NO as well as inhibition of phosphodiesterase type 5 led to increased myocardial tolerance of normoxic and chronically hypoxic rats. The effects of both interventions were not additive, suggesting that NO is included in cardioprotective signaling of CH. Second study continued in investigating molecular mechanisms underlying cardioprotection induced by CH. We showed that infarct size-limiting effect of adaptation to CH was accompanied by increased myocardial concentration of tumor-necrosis factor alpha (TNF-α) and TNF-α receptor R2. In the third study, we examined the effect of dexrazoxane (DEX), the only clinically approved drug against...
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The role of PGC1 in cardioprotective mechanisms
Jeřábková, Adéla ; Horníková, Daniela (advisor) ; Kolář, David (referee)
One of the leading causes of death worldwide is cardiovascular diseases. Researchers are, therefore, dealing with the mechanisms that induce a cardioprotection. Cardioprotection is a general pathophysiological term under which we understand myocytes protection against damage by ischemia and subsequent reperfusion impairment, inflammation, hypertension, and toxic and degenerative changes, including some types of apoptosis. One of the less common ways of cardioprotection is a cold adaptation. Adaptive thermogenesis is an important part of energy homeostasis and protection against obesity, metabolic disorder threatening heart. The PGC family of proteins plays a very important role in adaptive thermogenesis. This thesis summarizes the current state of literature in cold adaptation issues, especially the role of PGC1α and its effects at the cellular and tissue level. mRNA expression of PGC-1α is strongly induced in brown fat and skeletal muscles of mice exposed to cold. PGC-1α also increases the transcriptional activity of PPAR-γ and thyroid hormone receptor protein on UCP-1 (uncoupling protein). UCPs (uncoupling proteins) are small proteins localized to the inner side of the mitochondrial membrane to facilitate the transport of protons, which they release into concentration gradient without ATP...
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The role of sphingosin kinase in cardioprotection
Pospíšilová, Barbora ; Nováková, Olga (advisor) ; Kolář, David (referee)
Sphingosine-1-phosphate (S1P) is bioactive mediator with cardioprotective effect. Sphingosine kinase (SK) is a key enzyme in the synthesis of S1P. It exists in the two isoforms sphingosine kinase 1 and sphingosine kinase 2. Although SK1 has antiapoptotic feature and SK2 has proapoptotic feature both are crucial for the effect of S1P. S1P can act and affect the cellular faith by intracellular or extracellular functioning. Extracellular S1P binds and activates specific cell surface receptors on the plasma membrane. These receptors are members of the group of G protein-coupled receptors. There are tree subtypes of S1P receptors in the heart tissue (S1P1, S1P2, S1P3). Exogenous S1P increases viability of cardiomyocytes after myocardiacal ischemia/reperfusion injury (I/R). It also reduces the infarct size in isolated rat heart. During conditions of ischemic preconditioning (IPC) or postconditioning (IPOST) which consist of the short periods of ischemia before or after major ischemia insult generate S1P. Released S1P increased viability of the cell and faster recovery of hemodynamic functions in the heart tissue. Effects of S1P and its role in cardioprotection are explored in the genetically modified organisms mainly in the mouses. The evidence of the cardioprotective effect of S1P were experiments using...
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