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The role of lipids and ROS in cardioprotective mechanism of chronic hypoxia
Balková, Patricie ; Nováková, Olga (advisor) ; Drahota, Zdeněk (referee) ; Šmíd, František (referee)
The role of lipids and ROS in cardioprotective mechanism of chronic hypoxia Cardiovascular diseases, mainly ischemic heart disease is one of the most frequently cause of morbidity and mortality in developed countries. Therefore effective protection of the heart against ischemia and reperfusion injury is the crucial aim of experimental and clinical cardiology. One of the main streams of cardiovascular research is looking for possibilities of natural heart resistance augmentation. Adaptation to chronic hypoxia is one possibility how to protect the heart against ischemia-reperfusion injury. Chronic hypoxia increases resistance of the myocardium to acute deficiency of oxygen leading to vetricular arrythmias, postischemic contractile dysfunction and necrotic changes in the tissue. Recently, it has been shown that reactive oxygen species (ROS) play an important role in the cardioprotective mechanism of chronic hypoxia. It is known that oxidative stress has a harmful effect in acute ischemia-reperfusion however ROS generated during the adaptation to hypobaric intermittent chronic hypoxia play a role in the induction of cardioprotection. In this study, we demonstrated that adaptation of adult rats to chronic hypoxia increased the activity and protein abundance of manganese superoxide dismutase (MnSOD) in the...
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Mitochondrial cytochrome c oxidase: cyanide inhibition and role of assembly factor Surf1 defect
Nůsková, Hana ; Kalous, Martin (referee) ; Drahota, Zdeněk (advisor)
The activity of mitochondrial cytochrome c oxidase (COX) can be affected by either exogenous or endogenous factors. The most efficient and in the environment abundant compound that inhibits COX is cyanide. The very frequent cause of COX deficiency in humans is represented by a defect in the SURF1 gene. The mechanism of cyanide inhibitory effect on COX as well as the conditions for its recovery are not yet fully explained. Three parameters of COX function, namely the transport of electrons (oxygen consumption), the transport of protons (mitochondrial membrane potential, m) and the enzyme affinity to oxygen (p50 value), were studied with regard to the inhibition by KCN and its reversal by pyruvate. The function of COX was analysed in intact isolated rat liver mitochondria, both within the respiratory chain and as a sole enzyme, using succinate or an artificial electron donor ascorbate + TMPD as a substrate. 250 M KCN completely inhibited both electron- and proton-transporting function of COX, and this inhibition was reversible as proved with washing of mitochondria. The addition of 60 mM pyruvate induced the maximal recovery of both parameters to 60 - 80 % of original values. Using KCN in the low concentration range up to 5 M, a profound, 30-fold decrease of COX affinity to oxygen was observed....
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The Role of Uncoupling in Down-regulation of Reactive Oxygen Species
Ježek, Jan ; Žáčková, Markéta (advisor) ; Modrianský, Martin (referee) ; Drahota, Zdeněk (referee)
Uncoupling attenuates Complex I-derived superoxide production by accelerating electron flux and proton pumping within Complex I. However, under circumstances leading to hampered proton pumping pathway within Complex I, e.g. due to aberrant mutations of mtDNA encoding either ND2, ND4 or ND5 Complex I H+-pumping subunit, therapeutic strategy based simply on uncoupling would fail. Experimentally, hydrophobic amiloride EIPA mimicks the model of disabled H+-pumping. We show for the first time that EIPA is a real inhibitor of H+-pumping of mitochondrial Complex I. We searched for an agent that, unlike uncoupling, would be able to counteract oxidative stress associated with obstructed proton pumping of Complex I. Mitochondria-targeted ubiquinone MitoQ10 proved to be an effective antioxidant for this purpose when the rate of superoxide formation was high due to the electron flow retardation within Complex I. Because of its pro-oxidant properties, targeted delivery of MitoQ10 as a cure to the pathological tissue is necessary. Activation of mitochondrial phospholipase iPLA2 by mild oxidative stress can provide free fatty acid hydroperoxides as the cycling substrates for UCP2 that initiates mild uncoupling leading to the attenuation of reactive oxygen species (ROS) production, as a part of feedback regulatory loop of...
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