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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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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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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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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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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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Sirtuin 3 and its function in cardiac metabolism
Procházka, Marek ; Horníková, Daniela (advisor) ; Koňaříková, Eliška (referee)
SIRT3 is a NAD+ -dependent deacetylase, that is abundant in the heart and essentially regulates cellular processes in cardiomyocytes. SIRT3 positively modulates most of the enzymes and proteins in the intermediate metabolism in mitochondria, which supply the necessary ATP energy for the heart muscle and that are centers of metabolism in cardiomyocytes. In the mitochondria SIRT3 inhibits the formation of ROS by activating an antioxidant system. SIRT3 has significant anti-apoptotic, anti-hypertrophic and anti-fibrotic cardioprotective effects. Its activation is based on several drugs and natural substances that could be a promising therapeutic approach to the treatment of cardiovascular diseases, which are currently the leading cause of death of more than a half of the European population. However, more studies are required for better understanding the processes in which SIRT3 is involved. The aim of this work is to summarize the function of SIRT3 in mitochondrial metabolism and cardiac physiology. Key words: sirtuin 3, cardioprotection, metabolism, heart, mitochondria
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Novel Approaches To Protect The Heart Against Postischemic Failure
Hrdlička, Jaroslav ; Papoušek, František (advisor) ; Zicha, Josef (referee) ; Vízek, Martin (referee)
Ischemic heart disease and resulting heart failure (HF) belong to the leading causes of death in developed countries. In order to prevent HF and improve clinical outcome in patients with myocardial infarction, novel therapies are required to protect the heart against the detrimental effect of ischemic injury. Due to the failure to translate numerous available experimental cardioprotective strategies into clinical practice, the need for novel protective treatments persists. We have, therefore, tried to apply a novel approach to cardiac protection against the postischemic HF induced in rats by ligation of the coronary artery. For this purpose, we have studied (i) the preventive and therapeutic effects of adaptation to continuous normobaric hypoxia (CNH; 12% O2) and exercise training (ExT; treadmill running), and (ii) the possible cardioprotective potential of epoxyeicosatrienoic acid (EET)-based therapy in order to attenuate the postischemic HF in rats. Adaptation to CNH and ExT is known for their cardioprotection in acute ischemia/reperfusion (I/R) injury manifested as reduction of infarct size. EETs exert antihypertensive effects and thus seem to be perspective for the research in clinically relevant models of cardioprotection in hypertensive animals. Our results have revealed that: - CNH prior to...
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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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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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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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