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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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Cardioprotection induced by changes in abiotic environmental factors
Kubátová, Hana ; Vybíral, Stanislav (advisor) ; Žurmanová, Jitka (referee)
Cardiovascular diseases are one of the most frequent causes of death worldwide. Methods of limiting the ischemia-reperfusion injury, which occurs as a result of acute myocardial infarction (MI), have therefore been receiving significant attention. Preconditioning through ischemia application, cold exposure or physical exercise reduces the size of an infarction and the occurrence of ventricular arrhythmias. The exact mechanism behind this process has not yet been fully comprehended; nevertheless important roles are played by factors such as the maintenance of calcium homeostasis, the opening of ATP-dependent potassium channels (KATP) and the prevention of the Mitochondrial Permeability Transition pore (MPTP) opening. Chronic hypoxia and exercise have also been proven to have a cardioprotective effect, which is to be at least partially attributed to the intensified activity of antioxidant enzymes and the opening of KATP. During winter the risk of MI is increased for a wide range of patients. In winter swimmers, the stress caused by a cold stimulus is reduced. However, a mild stress is necessary to initiating cardioprotection. At present, there is unfortunately insufficient information available regarding the effects of long term cold adaptation on the size reduction of MI. Some studies suggest,...
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Role of phospholipases A2 in cardioprotection induced by continuous normobaric hypoxia in rat heart
Kyclerová, Eva ; Nováková, Olga (advisor) ; Novotný, Jiří (referee)
Recently, they are examined various means for activating the endogenous signalling pathways leading to increased resistance of the myocardium from ischemic/reperfusion (I/R) injury. One of them is the adaptation to chronic hypoxia, which has been shown to reduce the incidence and severity of ventricular arrhythmias, improves the recovery of postischemic contractile function of the heart and particularly reduces the extent of myocardial infarction. Since the function of the heart depends on the maintenance of membrane integrity of cardiomyocytes there are very important phospholipase A2 (PLA2) which are involved in the repair of cellular membranes. Also they are an important component of the protective signalling pathways because they cleave membrane phospholipids to produce lipid signalling molecules. Elucidate the role of PLA2 and the precise mechanism of action of signalling pathways leading to cardioprotection could be important for the prevention and treatment of cardiovascular diseases. Therefore, in this thesis we examined the influence of continuous normobaric hypoxia (CNH) to the relative representation of cardiac PLA2 (secretory - sPLA2IIA, calcium-independent - iPLA2, cytosolic - cPLA2α and its phosphorylated form - p-cPLA2α), and proteins involved in the activation and phosphorylation of...
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Cardiac ischemic tolerance of hypertensive rats
Jelínek, Jan ; Neckář, Jan (advisor) ; Sotáková, Dita (referee)
The aim of this thesis is to summarize current knowledge about the influence of the ischemic- reperfusion injury at the myocard of hypertensive subjects. First part of this thesis is focused on the description of ischemia, reperfusion and changes in the myocardial metabolism during these processes. These changes in the myocardial metabolism are for example necrosis or apoptosis of the myocardial cells. The second part describes the currently known cardioprotective phenomena. This part also compares their effects. The signalization of preconditioning, the second window of preconditioning and the postconditioning are described here in more details. Third part is focused on the description of the risk factors connected to the ICHS and hypertension. It describes also classes of hypertension, clinical and experimental methods of hypertension treatment, description of the laboratory breeds of hypertensive rats. In the last part of this thesis I describe the influence of hypertension on the I-R injury in current laboratory studies. In the most studies spontaneously hypertensive rats (SHR) were used. As a normotensive controls Wistar-Kyoto rats were mostly used. For some other experiments transgenic genetic rats (TGR) were used. Powered by TCPDF (www.tcpdf.org)
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Role of oxidative stress in cardioprotection induced by exercise.
Kyclerová, Eva ; Nováková, Olga (advisor) ; Kašparová, Dita (referee)
Cardiovascular diseases are the major cause of death in developed countries. It is known that heart muscle can activates endogenous protective pathways in response to stress, thereby increasing resistance against ischemia/reperfusion (I/R) injury. Protective pathways involve many signaling molecules and reactive oxygen species (ROS) play an important role among them. ROS are applied in cardioprotection induced by various stimuli, such as chronic hypoxia, preconditioning and also physical exercise. It has been demonstrated that regular physical exercise naturally leads to the positive adaptation to protect heart against injury. The balance between production of ROS and their removal by antioxidant protection system is important for the right functioning of the heart. The overproduction of ROS occurs in pathological conditions such as an I/R leading to oxidative stress contributing to subsequent damage of heart. ROS may contribute not only to the injury but in the mild concentrations, resulting for example from physical exercise, ROS are important signaling molecules involved in series of events leading to cardioprotection. Slightly increased oxidative stress protects the heart by increasing the capacity of antioxidant system, stimulates angiogenesis, activates mitochondrial biogenesis and physiological...
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