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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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Role of KCNQ channels in response of the pulmonary circulation to hypoxia
Šedivý, Vojtěch ; Herget, Jan (advisor) ; Melenovský, Vojtěch (referee) ; Neckář, Jan (referee)
Reaction of pulmonary vascular bed to hypoxia is different than in systemic vasculature. Acute ventilatory hypoxia constricts pulmonary arteries (HPV), diverts blood to better oxygenated alveoli and optimises arterial pO2. Chronic hypoxia causes pulmonary hypertension (HPH) and exposure to hypoxia at birth (perinatal hypoxia) results in longterm changes of pulmonary vasculature, which makes it more susceptible to develop pulmonary hypertension in adulthood. Reaction of pulmonary artery smooth muscle cells (PASMCs) to hypoxia involves membrane depolarization by inhibition of voltage gated potassium channels (Kv). Among them KCNQ (Kv7) channels have biophysical properties (low voltage threshold for activation and lack of inactivation during sustained depolarization) which suggest them to play a key role in hypoxic response. Specific KCNQ channel inhibitor linopirdine primes HPV in saline perfused lungs, but in not primed lungs does not cause vasoconstriction, it behaves in the same way as acute ventilatory hypoxia. Moreover, in primed lungs linopirdin potentiates HPV and prevents non- specific Kv inhibitor 4-aminopyridine to potentiate HPV. It seems, that KCNQ channel inhibition has a key role in HPV. In rats exposed to hypoxia for 3-5 days (normobaric chamber, FiO2 0,1) we examined relationship of...
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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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