Yu. P. Kozlov

The role of lipid peroxidation in pathogenesis of ischemic damage and the antioxidant protection of the heart

SummaryA working hypothesis on pathogenesis of ischemic heart damage has been proposed. According to this hypothesis, a crucial role in conversion of reversible damage into irreversible damage is played by cardiomyocyte membrane destruction caused by the so-called “lipid triad”. The latter comprises activation of lipid peroxidation, activation of phospholipases, and the degergentlike action of excessive amounts of free fatty acids and lysophospholipids. Marked activation of lipid peroxidation in experimental myocardial infarction, as well as reoxygenation following transitory ischemia, have been demonstrated. The proposed hypothesis and experimental data underly successful application of synthetic free radical scavengers (antioxidants) for heart protection against experimental myocardial infarction, transitory ischemia, and emotional, painful stress.ZusammenfassungIn der vorliegenden Studie wird eine Arbeitshypothese zur Pathogenese der ischämischen Herzschädigung aufgestellt. Nach dieser Hypothese ist ein entscheidender Faktor für den Übergang von der reversiblen zur irreversiblen Schädigung eine Membrandestruktion der Herzmuskelzellen, welche durch sog. Lipid-Triaden verursacht wird. Letztere beinhaltet eine Aktivierung der Lipid-Peroxidation und der Phospholipase sowie eine Detergenz-ähnliche Wirkung exzessiver Mengen von freien Fettsäuren und Lysophospholipiden. Eine ausgepräge Aktivierung der Lipid-Peroxidation beim experimentellen Herzinfarkt sowie eine Reoxigenierung nach vorübergehender Ischämie wurden demonstriert. Die vorgelegte Hypothese und die experimentellen Daten legen eine Anwendung von Radialfängern (Antioxidantien) nahe für die Protektion des Herzens gegen experimentellen Myokardinfarkt, vorübergehende Ischämie und emotionalen Streß bei Schmerzsituationen.

Accumulation of lipid peroxidation products and depression of retinal electrical activity in vitamin E-deficient rats exposed to high-intensity light

: It was shown in experiments on dogs that after 4-hour hypovolemic hypotension the content of total RNA in brain cortex and myocardium homogenates decreased. In the liver, there was a significant decrease both in RNA and DNA content. In the postresuscitation period, the content of nucleic acids in the myocardium returned to normal after 14--21 days, and that in the liver after 3--4 months. The gray matter of the brain manifested a delayed lowering of DNA content (after 14--21 days), and the level of nucleic acid did not return ot normal over 3--4 months after resuscitation.

Ischemic damage to the sarcoplasmic reticulum of skeletal muscles: The role of lipid peroxidation

The development of ischemia was shown to be accompanied by inhibition of the Ca2+ enzyme transport system (ETS) (a decrease in the Ca2+/ATP ratio and in activity of Ca2+-dependent ATPase), which correlates with accumulation of the primary and secondary molecular lipid peroxidation products (POL) in vivo and in the membranes of the sarcoplasmic reticulum (SR) of the skeletal muscles. Administration of antioxidants (2,6-di-tert-butyl-4-methylphenol, α-tocopherol) prevents activation of POL in the ischemic muscle and partially protects the Ca2+ ETS against injury. Restoration of the blood flow after prolonged ischemia leads to further inhibition of the Ca2+ ETS while the concentration of POL products remains unchanged.

Use of interferon-α-induced dendritic cells in the therapy of patients with malignant brain gliomas

Clinical and immunological analysis of the efficiency of combined immunotherapy with the use dendritic cells for the treatment of malignant glioma of the brain was carried out. Dendritic cells generated in the presence of granulocyte-macrophage CSF and IFN-α retain their functional characteristics in patients with gliomas, which suggests the possibility of their use for the treatment of malignant tumors (glioma) of the brain. Combined therapy using interferon-induced dendritic cells was associated with generation of antigen-specific immune response during vaccinations. The results indicate satisfactory tolerance of combined immunotherapy using dendritic cells and the absence of toxic side effects at the stage of adoptive immunotherapy and at the stage of vaccinations with dendritic cells. Clinical trials showed that vaccinations with dendritic cells included into combined immunotherapy improved the quality of life and survival of patients with malignant gliomas.

Effects of products of phospholipid hydrolysis by phospholipases on rhodopsin thermal stability in photoreceptor membranes

Abstract The decrease in the thermal stability of rhodopsin in sea teleost fish ( Theragra chalcogramma ) retinal rod outer segments (ROS) is strictly correlated with the increase in the amount of phospholipid hydrolysis products. The addition of exogenous unsaturated fatty acids to the ROS suspensions cause an increase of the rhodopsin thermal denaturation rate constants and a decrease of the E a value. On the other hand, saturated fatty acids at temperatures below their melting points and lysophosphatidylcholine produce practically no effect. The thermal stability of T. chalcogramma rhodopsin may be considerably enhanced when endogenous or exogenous fatty acids are eliminated by washing the ROS suspensions with a solution of fatty acid free bovine serum albumin. The role of phospholipids and their hydrolysis products in the thermal stability of rhodopsin is discussed.

Disturbances of the Ca++ transport enzyme system in membranes of the sarcoplasmic reticulum caused by hydroperoxides of phospholipids and of fatty acids

The hydroperoxide (HP) of phosphatidylethanolamine, if added to a suspension of vesicles of the sarcoplasmic reticulum (SR), was shown to have a weak activating effect on Ca-dependent ATPase and to increase the permeability of SR membranes for Ca++, measured during activity of the enzyme. HP of linoleic acid did not affect the parameters of the Ca++ transport enzyme system, the activity of Ca++-dependent ATPase, the Ca/ATP ratio, or the rate of outflow of Ca++ in SR membranes on account of the low level of its incorporation into SR fragments. It is concluded that among the primary molecular peroxidation products (HP of free fatty acids, HP of phospholipids), induced both in vitro (by the Fe+++ascorbate system) and in vivo (ischemia, avitaminosis-E), only phospholipid HP is an effective modifier of Ca++ transport in SR membranes.

3H-serotonin and3H-diazepam binding and lipid peroxidation in brain cell membranes

The action of extracellular signals (hormones, mediators) on target cells is effected through the binding of the ligand substances with receptors on the outer surface of the plasma membrane, leading to activation or inhibition of the effector system (enzyme, ionophore, etc.) [5]. An essential role in this interaction between ligands and membrane receptors is played by the lipid microenvfi:onment, which provides the necessary protein conformation for binding the ligand [6]. A productive approach to the study of the role of lipids in m aintenance of the functional activity of membrane receptors is the chemical modification of the lipid bilayer [7]. A physiologically important process in chemical modification of lipids is lipid peroxidation (LPO), which in vivo is activated by factors such as hyperoxia, stress, avitaminosis E, etc. [31.

Does α-tocopherol interact with the active site of cytochrome P-450 in liver microsomes?

: Inoculation of rabbits with permanent B-cell line cultures obtained from Stumptailed Macaques M. arctoides (MAL) which contain lymphotropic herpesvirus and C-type particles has led to the development of generalized lymphomas. The lymphoma cells had rabbit karyotype and did not contain surface an cytoplasmic immunoglobulins. Permanent suspension of lymphoid cell line independent of growth factors was obtained from rabbit lymphoma. The serum of a rabbit with lymphoma transmitted from another rabbit with MAL-induced lymphoma did not react with virus-negative human Raji cells when tested in immunofluorescence. But this serum reacted positively with cytoplasmic antigens of simian 594S-F9 cells (producing lymphotropic herpesvirus and two types of retroviruses, namely, endogenous C-type and HTLV-I-like) and human C91-PL cells (producing HTLV-I). The results obtained demonstrated high oncogenicity of the viruses produced by simian permanent cellular MAL lines for rabbits.

Lipid peroxidation and retinal injury in stress

Emotional-painful stress (EPS) regularly leads to generalized activation of lipid peroxidation (LPO), and this is expressed as accumulation of LPO products in various tissues: the brain, heart, muscles, etc. [5, 6]. Activation of LPO has been shown to be a key stage in the pathogenesis of stress injury to the myocardium, and LPO inhibitors can prevent both the accumulation of LPO products and the development of the complex of stress injuries to the heart [7]. Meanwhile the role of accumulation of LPO products in the brain, induced as a result of EPS, has not been studied. A convenient object with which to study this problem is the retina, which develops in mammals from brain tissue and contains high concentrations of polyene lipids, undergoing LPO with a high reaction velocity [4]. Changes in retinal function can be easily and conveniently recorded as the electroretinogram (ERG) in response to photic stimulation. Psychogenic (stressor in origin) disturbances of vision also have been the subject of research in clinical ophthalmology for a long time [i]. However, the effect of stress on metabolism and functions of the retina, the peripheral part of the visual analyzer, has not previously been investigated.

Effect of stress on cardiomyocyte transmembrane potential of the working heart and its recovery after hypothermia

Emotional-painful stress in rats was shown to decrease insignificantly transmembrane cardiomyocyte potential (TCP) measured in isolated hearts. The recovery of TCP following its depression due to the preparation cooling was twice slower in stress-exposed than in control animals. This is in keeping with the data on stress-induced disturbances of Na, K-ATPase activity (an enzyme playing a leading role in TCP maintenance). It is suggested that the disturbance in cation pump function activity plays a certain role in the onset of arrhythmias and cardiac fibrillation during stress.