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Atherosclerosis risk factors and macrophage polarization in adipose tissue
Králová, Anna ; Poledne, Rudolf (advisor) ; Vrablík, Michal (referee) ; Zicha, Josef (referee)
Atherosclerosis is a major cause of cardiovascular disease, and the pro-inflammatory state stimulates the process of atherogenesis. Since the 1990s, it has become clear that adipose tissue has not only an endocrine function, but it is also a very important immune organ due to the presence of various immunocytes with high cytokine secretion. Local resident macrophages represent a major component in the development of this inflammation. Due to our inclusion in the unique transplantation program at IKEM, which ensured availability of peroperatively harvested adipose tissue and its subsequent and immediate analysis, we were able to characterize the different subpopulations of monocytes/macrophages and classify macrophages into pro- and anti-inflammatory populations based on the differential expression of surface markers. From subcutaneous (SCAT), perivascular (PVAT), and visceral (VAT) adipose tissue samples from healthy living kidney donors (LKD), we analyzed the macrophage phenotype after obtaining the stromal fraction by flow cytometry. At the beginning of the experiments, we chose the calprotectin molecule as a proinflammatory marker. However, in subsequent experiments described herein, we chose a different route and selected the CD16 receptor to determine the proinflammatory phenotype. This...
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Excitation-Contraction and Excitation-Transcription Coupling in Vascular Smooth Muscle Cells: Alterations in Experimental Hypertension and Vascular Remodeling
Misárková, Eliška ; Zicha, Josef (advisor) ; Hock, Miroslav (referee)
Vascular smooth muscle cells (VSMCs) express considerable phenotype plasticity. They are able to change their phenotype in vivo if necessary. It is important to know that during this phenotype switch the expression of transport proteins and channels is modified, which results in significant alteration of Ca2+ signaling in smooth muscle cells. In differentiated cells, which represent contractile phenotype, there are dominant rapid, transient events in intracellular Ca2+ concentration (Ca2+ i), while the resting cytosolic Ca2+ i concentration is low. In differentiated cells these Ca2+ i events are mainly caused by two components of the Ca2+ signalling pathways: 1) extracellular Ca2+ influx via L-type voltage-gated Ca2+ channels (L-type VGCC) in plasma membrane, and 2) depletion of intracellular Ca2+ stores via ryanodin receptors located on sarcoplasmic reticulum. Rapid Ca2+ i oscillations are quickly reduced by numerous Ca2+ ATPases of sarco/endoplasmic reticulum and plasma membrane. Proliferating vascular smooth muscle cells are characterized by a long-lasting Ca2+ i oscillations accompanied by sustained elevation of basal intracellular Ca2+ concentration. During phenotype switch from contractile phenotype to proliferative phenotype there is decreased Ca2+ ATPase activity, and store-operated Ca2+...
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The role of RhoA/Rho kinase signalling pathway in the regulation of blood pressure in normotensive and hypertensive rats
Brunová, Aneta ; Zicha, Josef (advisor) ; Wasková, Petra (referee)
Evidence is accumulating that point to a major role of Rho kinase in arterial pathophysiology. Rho kinase is a key enzyme in calcium sensitization in vascular smooth muscle cells. Calcium sensitization is characterized as an increase in vascular contractility in the conditions of constant cytosolic calcium level. Inhibitors of Rho-kinase exert beneficial effects on the cardiovascular system, mainly by lowering vascular contractility. This thesis summarizes the current progress in understanding of the signaling pathways involved in the control of peripheral resistance of spontaneously hypertensive rats (SHR). It is evident that enhanced sympathetic activity and abnormal regulation of ion channel activity collectively contribute to high blood pressure maintenance in SHR.
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Neural mechanisms in the pathogenesis of spontaneous hypertension in the rat
Vavřínová, Anna ; Zicha, Josef (advisor) ; Haluzík, Martin (referee) ; Neckář, Jan (referee)
Both sympathoneural and sympathoadrenal systems are involved in the regulation of arterial blood pressure and in the pathogenesis of hypertension. Spontaneously hypertensive rats (SHR), the mostly used animal model of genetic hypertension, is characterized by multiple molecular, morphological and functional alterations at different levels of sympathoneural and sympathoadrenal systems. The study of young prehypertensive SHR allows to reveal the abnormalities preceding hypertension development, whereas adult SHR with established hypertension offers a better model for the treatment of human essential hypertension. The aim of my PhD Thesis was to describe abnormalities in sympathoneural and sympathoadrenal systems in SHR under different conditions. Firstly, ontogenetic differences which might contribute to hypertension development were determined. Secondly, the effect of chemical sympathectomy induced by guanethidine in adulthood on cardiovascular parameters and on the compensatory mechanisms counteracting the reduction of blood pressure were studied. Thirdly, stress-induced cardiovascular response and stress-induced changes of sympathoneural and sympathoadrenal systems were described in adult SHR. My Thesis brought several important results. The increased adrenal catecholamine content and the...
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Role of Potassium Channels in the Regulation of Vascular Smooth Muscle Tone
Bencze, Michal ; Zicha, Josef (advisor) ; Moravec, Jan (referee)
In smooth muscle cells, potassium channels play an important role in the regulation of the membrane potential of smooth muscle cells, which is closely related to vascular tone. Four different types of K+ channels have been described in vascular smooth muscle cells. Voltagegated K+ channels (KV), which can be open by depolarization. Calcium-activated potassium channels (KCa), from the same gene family, are voltage dependent, and can be activated also by elevated concentration of intracellular Ca2+. Inward rectifying channels (KIR) display negative slope conductance. These channels amplify potassium flow and function as an extracellular K+ sensor. ATP-sensitive K+ channels (KATP) channels provide a link between cell metabolism and membrane potential. Function of K+ channels is also important in endothelium, which produces many vasodilatators and vasoconstrictors. Abnormal expression profile of K+ channels is part of vascular cell membrane remodeling.
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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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The role of arachidonic acid metabolites in regulation of blood pressure in experimental models of angiotensin II- dependent hypertension
Jíchová, Šárka ; Červenka, Luděk (advisor) ; Zicha, Josef (referee) ; Štengl, Milan (referee)
Introduction: Two major product groups originate from the arachidonic acid metabolic pathway of cytochromes P450: epoxyeicosatrienoic acid (EETs) and 19 and 20-hydroxyeicosatetraenoic acid (19- and 20-HETE). These metabolites play an important role in the regulation of blood pressure, inflammatory responses, regulation of sodium excretion and other crucial physiological processes. Hypothesis: Our studies were based on the hypothesis that abnormalities in the production and function of these cytochrome P450 metabolites significantly contribute to the pathophysiology of hypertension development, in particular in the angiotensin II-dependent models. Objective: To investigate if the increased bioavailability of the above-mentioned metabolites in the kidney tissue will result in blood pressure reduction in the ANG II - dependent rat model of hypertension. Methods: The two methods to increase the concentration of EETs was chosen. In the first part of the study, we administered a soluble epoxide hydrolase inhibitor cAUCB [cis-4- [4- (3-adamantan-1-yl- ureido) cyclohexyloxy] benzoic acid, at a dose of 26 mg.l-1 administered in drinking water], an enzyme responsible for inactivation of biologically active forms of EETs. In the second series of the experiments we applied a synthetic EET analogue, called...
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Neural mechanisms in the pathogenesis of spontaneous hypertension in the rat
Vavřínová, Anna ; Zicha, Josef (advisor) ; Haluzík, Martin (referee) ; Neckář, Jan (referee)
Both sympathoneural and sympathoadrenal systems are involved in the regulation of arterial blood pressure and in the pathogenesis of hypertension. Spontaneously hypertensive rats (SHR), the mostly used animal model of genetic hypertension, is characterized by multiple molecular, morphological and functional alterations at different levels of sympathoneural and sympathoadrenal systems. The study of young prehypertensive SHR allows to reveal the abnormalities preceding hypertension development, whereas adult SHR with established hypertension offers a better model for the treatment of human essential hypertension. The aim of my PhD Thesis was to describe abnormalities in sympathoneural and sympathoadrenal systems in SHR under different conditions. Firstly, ontogenetic differences which might contribute to hypertension development were determined. Secondly, the effect of chemical sympathectomy induced by guanethidine in adulthood on cardiovascular parameters and on the compensatory mechanisms counteracting the reduction of blood pressure were studied. Thirdly, stress-induced cardiovascular response and stress-induced changes of sympathoneural and sympathoadrenal systems were described in adult SHR. My Thesis brought several important results. The increased adrenal catecholamine content and the...
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The role of epoxyeicosatrienoic acids in blood pressure and renal function regulation in the experimental models of hypertension
Honetschlägerová, Zuzana ; Čertíková-Chábová, Věra (advisor) ; Zicha, Josef (referee) ; Maxová, Hana (referee)
Introduction: Epoxyeicosatrienoic acids (EETs) are converted by the enzyme soluble epoxid hydrolase (sEH) to the biologically inactive dihydroxyeicosatrienoic acids (DHETs). EETs are significantly involved in the control of blood pressure, they influence vascular tone and renal transport mechanism. sEH inhibitor reduce blood pressure by increasing the bioavailability of EETs in many models of hypertension. Aim of the study: To determine that sEH inhibitor decreases blood pressure and improves the renal function during the development of malignant hypertension in transgenic rats after the induction of the mouse renin gene. Methods: Hypertension in Cyp1a1-Ren-2 transgenic rats was induced through a dietary administration of the natural xenobiotic indole-3-carbinol (I3C, 0.3 %) for 3 and 11 days. I3C activates the renin gene. At the same time, during a three-day induction of hypertension, the inhibitor of nitric oxide synthase L-NAME (600 mg/l) was administered in drinking water. The sEH inhibitor c-AUCB was given in drinking water at a dose of 13 or 26 mg/l, starting 48 hours before the initiation of I3C and L-NAME administration. Radiotelemetric measurement of blood pressure was performed and renal excretory parameters were monitored in the conscious animals. The effects on renal hemodynamics and...
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