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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 C-reactive protein in cardiac ischemic tolerance
Perglerová, Aneta ; Neckář, Jan (advisor) ; Vebr, Pavel (referee)
Ischemic heart disease (CHD) is a set of pathophysiological states, disorders of blood flow and oxygen supply of the myocardium due to vascular constriction or thrombus blockage. Inflammation plays an important role in CHD. The inflammatory response is associated with the synthesis of acute phase proteins in the liver such as C-reactive protein (CRP). CRP plays an important role in acute forms of CHD such as myocardial infarction (MI). The development of CHD may be supported by the occurrence of some of the risk factors (eg. atherosclerosis, hypertension, plasma CRP). Increased CRP levels may support the initiation of atherosclerotic plaque formation as well as in the case of hypertension the presence of CRP increases the risk of developing CHD. The healing proces after acute MI is accompanied by an inflammatory phase where CRP occurs naturally and CRP is important to accelerate inflammation. There may be a situation which inflammation goes into a chronic phase because it is not terminated in time, with constant CRP synthesis. High levels of CRP may decrease the prognosis after MI. The elevated plasma CRP has a negative effect on the expansion of MI and the associated ventricular dilatation, which may result in a rupture of the cardiac wall. Hypertrophy is the compensatory mechanism of the...
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The role of hypoxia inducible factor-1α in the progression of chronic heart failure
Kordač, Petr ; Neckář, Jan (advisor) ; Vebr, Pavel (referee)
Transcription factor hypoxia inducible factor-1α (HIF-1α) is a key regulator of physiological and cellular mechanisms to adapt to deficiency of oxygen. In hypoxia (or ischemia) HIF-1α level increases as HIF-1α-degrading enzymes prolyl hydroxylases are inactive due to low oxygen level. HIF-1α plays also essential role in triggering cellular protection and metabolic alteration during pathophysiological conditions in the heart. It has been suggested that stabilization of HIF-1α in myocardium may prevent deleterious remodelling induced by various forms of chronic heart failure (CHF). The project aims to outline current knowledge about the role of HIF-1α in the progression of CHF.
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The effect of maternal diabetes on embryonic cardiovascular development and fetal programing
Čerychová, Radka ; Pavlínková, Gabriela (advisor) ; Nováková, Olga (referee) ; Neckář, Jan (referee)
Maternal diabetes mellitus negatively affects embryonic development and increases the risk for congenital malformations. Besides direct teratogenicity, diabetic intrauterine milieu can predispose an individual to chronic diseases later in life, including cardiovascular diseases, obesity, and diabetes mellitus, in a process termed fetal programing. Molecular mechanisms of embryonic and fetal responses to maternal diabetes are still not fully elucidated. Using mouse model, we show that maternal diabetes induces gene expression changes in the hearts of developing embryos. The most significant changes in the expression of 11 selected genes were detected at the developmental stage associated with completion of cardiac septation, myocardial mass expansion, and increased insulin production in the embryonic pancreas. These affected genes encode products involved in the epithelial-to-mesenchymal transition, a crucial process in heart development. Using immunohistochemistry, we detected increased hypoxia in the diabetes-exposed hearts at the critical stage of cardiac development. Correspondingly to increased hypoxia, the expression of hypoxia-inducible factor 1α (HIF1α) and vascular endothelial growth factor A was increased in the heart of diabetes-exposed embryos. Based on our results indicating the...
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Gender differences in myocardial apoptosis of the patients after heart tranplantation.
Smetana, Michal ; Szárszoi, Ondrej (advisor) ; Brát, Radim (referee) ; Neckář, Jan (referee)
Gender differences in myocardial apoptosis of the patients after heart transplantation Background: Many functions of the cardiovascular apparatus are influenced by gender. The aim of our study was to find out the sensitivity to perioperative ischemia of the donor female and male myocardium; and determine how the organism affects the donor myocardium of the other sex after heart transplantation (detection of apoptosis), and whether the investigated biomarkers can predict primary graft dysfunction (PGD). Methods: The research was divided into three prospective studies. The Study 1 included 81 patients undergoing heart transplantation from September 2010 to January 2013. Patients were divided into two groups according to male allograft and female allograft. In order to prove myocardial necrosis the high-sensitive cardiac troponin T (hs-cTnT) method was used. Apoptosis was determined by immunohistochemical detection of caspase-3, Bcl-2, and by the TUNEL method. The Study 2 includeded 58 patients divided into four groups according to gender; both of the recipient and the donor. Apoptosis (caspase-3, Bcl-2, TUNEL) was analysed in these groups during the two-year follow-up. Into Study 3 64 patients were involved. We investigated the relationship in between these biomarkers and the development of PGD after...
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The role of calcium influx and calcium sensitization in contraction of isolated arteries of normotensive and hypertensive rat
Bencze, Michal ; Zicha, Josef (advisor) ; Neckář, Jan (referee) ; Chalupský, Karel (referee)
Vascular resistance is mainly determined by the contraction of vascular smooth muscle (VSM), which is regulated by the phosphorylation of myosin light chain (MLC). VSM contraction is initiated by calcium influx into the VSM cells, which is mediated by transient receptor potential (TRP) channels and L-type voltage- dependent calcium channels (L-VDCC). On the other hand, calcium sensitization is a mechanism enhancing vascular contractile response at a given level of intracellular calcium by RhoA/Rho kinase pathway-mediated inhibition of myosin light chain phosphatase. In this thesis I present the data about i) the role of TRP channels in the mechanisms of vascular smooth muscle contraction, ii) enhanced contractility of arteries from spontaneously hypertensive rats (SHR), and iii) the differences in contraction of arteries from normotensive and hypertensive rats related to the role of RhoA/Rho kinase pathway in three types of experimental hypertension (SHR, Ren-2 transgenic rats and salt-sensitive Dahl rats). In the study concerning TRP channels, I compared the effects of three commonly used non-selective TRP channels inhibitors (2-APB, SKF-96365, FFA) on isolated arteries. Among them 2-APB was the most interesting because the observed inhibitory effects of 2-APB were dependent on the type of...
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Organization of myofibrillar PCr/CK system in skeletal muscle
Žurmanová, Jitka ; Mejsnar, Jiří (advisor) ; Nováková, Olga (referee) ; Neckář, Jan (referee)
5. SUMMARYOFRESULTES Áll resultshavebeenpublishedor acceptedin joumalswith IF. Ite list of publicďionis enclosedin thechaoter6. 1) Lcvcls of cneigr-rclated metabolitcsin intect and isolated pcrfuscd-supcrfused rrt ske|ctálmusc|e*(ŠteÍleta],1991) AdenosineS'.triphosphate(ATP), phosphocreatine(PCr), creatirre(Cr), ínorganicphosphate (Pi),lactate(LAC), pyruvate(PYR) andglycogenasglucose(GLU) weredeterminedandfree adenosineS'-diphosptrate(ADP) was calculatedtom ATP:creatinephosphokinase(CPK) reactionin the gracilis muscleof cold.acc|imatedrďs in vivo. and in completelyisoIated mrsc|esundermediumperfusionandzuperfusionínvito, rsing thefreeze-clampingmetlrcd. Themeanin vivo leve|s(pmoVgw.w.)were:ATP 4.8'PCr 12.0.Cr 7,8'Pi ló.l' LAc l.6' PYR 0.09,GLU 22.9,ADP 0,62x t0-3.[solationof the muscle(about11min of anox'a fo|lowedby perfision irrthe air with a highpo2 Inedium)decreasedmacroergicphosphďe levels(ATP 3.0.PCr 8.3).Inisolatedmusclesperfusedwitha highpO2medium(99kPaOz, perflrion rate70 pl/mitt)andsimultaneouslysupeďusedwitha low po2medium(ó.2kPao2' 2.3mVmin)at28oC in vitrothelevelsof metaboliteswere(pmoUgw.w.):ATP 3.1,PCr 8.5, Cr 5.ó.Pi 9'2, |Ac 2.|' PYR 0.l9. GLU 6.6'ADP 0.44x l0(.]).Themeansteadyoxygen upuke of the íso|atedmusclewas 97 nmol 02 x min.l x g.l w.w. Ttrus.thelevelsof macroergicphosphatesand their...
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Cardiac ischemic tolerance in rats subjected to adaptation to chronic hypoxia and physical exercise: the role of TNF-alpha.
Svatoňová, Anna ; Neckář, Jan (advisor) ; Maxová, Hana (referee) ; Szárszoi, Ondrej (referee)
Cardiovascular diseases represent the most important health risk factors because they are responsible for more than 50% of total mortality. Among them, the ischemic heart disease is leading cause of mortality. From the whole spectrum of different cardioprotective phenomena we have selected: 1) adaptation to chronic normobaric hypoxia (CNH) as the traditional experimental model in our laboratory area and 2) protective effect of exercise which in recent years represents promising and clinically relevant protective mechanism. The whole thesis is based on two studies. Aim of the first study was to characterize the expression of the main pro-inflammatory cytokine, TNF-α, in hearts of rats adapted to CNH. Chronic TNF-α inhibition by infliximab was used for discovering of certain role of TNF-α in CNH. We showed that increased myocardial level of TNF-α during adaptation to CNH was contributed via its receptor TNFR2 and nuclear factor κB-dependent activation of protective redox signalling with increased antioxidant defence. This adaptive pathway participates on the infarct size-limiting effect of CNH. Aim of the second study was find out whether exercise training and CNH could play synergy in cardiac protection in rats model. We reported that CNH and exercise reduced infarct size but their combination...
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