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Oxidative stress and its prevention in adriamycin-induced heart failure
OXIDATIVE STRESS AND ITS PREVENTION ADRIAMYCIN-INDUCED HEART FAILURE P. K. Singal, N. Iliskovic, T. Li, and I. Danelisen Institute of Cardiovascular Sciences, Universiv , Manitoba, Winnipeg, Canada
INVOLVEMENT OF REACTIVE OXYGEN SPECIES IN CYCLIC STRAIN-INDUCED ENDOTHELIN-1 GENE EXPRESSION IN ENDOTHELIAL CELLS T. H. Cheng, N. L. Shih, D. L. Wang, and J. J. Chen Graduate Institute of Life Sciences, National Defense Medical Center and institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan: R.O.C.
IN
of
Congestive heart failure (HF) in rats was produced by repeated injections (6 x 2.5 mg/kg, i.p., over 2 weeks) of adriamycin (ADR) - an effective antitumor antibiotic. Several hemodynamic and morphological characteristics in this HF were found to be in common with those seen in cancer patients treated with anthracyclines. The HF is likely mediated by increased oxidative stress, Pre- and concurrent-treatment of the animals with probucol (12 x 10 mg/kg), a lipid-lowering drug and an antioxidant, against ADR-induced offered complete protection cardiomyopathic changes with a significant normalization of the oxidative stress. Probable contribution of lipidlowering properties of probucol in preventing HF was also studied by comparing its effect with that of lovastatin another lipid-lowering drug. Experiments to examine the effects of probucol on antitumor properties of ADR revealed that the proposed combination did not compromise antitumor efficacy of the drug. Thus, the combination therapy using ADR and probucol has a great potential for clinical application. The study also showed that increased oxidative stress and reduced antioxidant reserve contribute in the pathogenesis of HF.
Since strain induced a sustained elevated level in intracellular reactive oxygen species (ROS), we hypothesised that the ROS could be a modulator in cyclic strain-induced endothelin- 1 (Et- 1) gene expression in endothelial cells. Cultured endothelial cells grown on a flexible membrane base were deformed by vacuum to 25% of maximum strain at 60 cycles/min for various periods. Human umbilical vein endothelial cells (HUVEC) subjected to strain showed increased Et-l secretion and intracellular Et-l mRNA level compared with unstrain control cells. Pretreated HLJVEC with antioxidant, catalase (300 U/ml) or 1,3-Dimethyl-2-Thiourea (DMTU; 0.1 mM), abolished the strain-induced Et-l release and intracellular Et-l mRNA level. When transfected the fusion plasmids containing Et-l 5 ’-flanking sequence (4.4 kb) and the chloramphenicol acetyltransferase gene into bovine aortic endothelial cells, cells strained for 6 hours allowed maximal transcription, whereas pretreatment with catalase also decreased Et-l promoter activity. These data indicate that ROS involved in cyclic strain-induced Et-l gene expression in endothelial cells.
(Supported by the Manitoba Heart and Stroke Foundation.)
THE STATE OF PROCESSES OF LIPID PEROXIDATION AND HEMOSTASIS IN PLAGUE INTOXICATION N.Chesnokova, G.Afanasieva, E.Ponukalina Medical Universiw, Saratov, Russia
GENE EXPRESSION AND ATHEROSCLEROSIS S. YlCHerttuala A. I. Virtanen Institute, University of Kuopio, Finland Oxidative modification of low density lipoprotein (LDL) plays an important role in atherogenesis. Oxidized LDL has several effects on gene expression on the arterial wall cells. In vitro, minimally oxidized LDL is a potent inducer of monocyte chemotactic protein-l stimulating factor-l colony (MCP-I), macrophage (MCSF-1) and tissue factor (TF). If formed under endothelium, minimally oxidized LDL can stimulate monocyte binding to endothelium, monocyte influx into the artery wall and thrombogenic properties of endothelium. When LDL is oxidized more extensively it becomes cytotoxic to arterial wall cells. Extensively oxidized LDL could lead to a dysfunction and/or injury of endothelial cells. Extensively oxidized LDL also affects plateletderived growth factor (PDGF) expression by arterial wall cells and inhibits endothelial cell-derived relaxing factor (EDRF) activity. In summary: When LDL is oxidized it aquires several atherogenic properties which can influence cellular lipid metabolism and various other functions of the arterial cells. The identification of LDL oxidation as one of the key events in the pathogenesis of atherosclerosis offers an interesting possibility to reduce atherosclerosis by antioxidants and other compounds that protect LDL against oxidative damage.
In experiments on white rats in plague intoxication produced by intraabdominal administration of vaccine strain EB, we observed the accumulation of lipid hydroperoxides and malonic dialdehyde in blood plasma, erythrocytes and some inner organs, the decrease of the level of sulfhydryl groups of thiol combinations in blood serum despite the increase in the activity of blood superoxide dismutase and catalase. At the same time we noted hypercoagulation shears in the early stage of intoxication to be replaced in succession by hypocoagulative disorders in the background of stable activation of anticoagulant mechanisms and tibrinolysis system. A definite correction of hemostasis disorders and lipid peroxidation process is achieved when using antihypoxants.
17
INVOLVEMENT OF REACTIVE OXYGEN SPECIES IN CYCLIC STRAIN-INDUCED ENDOTHELIN-1 GENE EXPRESSION IN ENDOTHELIAL CELLS T. H. Cheng, N. L. Shih, D. L. Wang, and J. J. Chen Graduate Institute of Life Sciences, National Defense Medical Center and institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan: R.O.C.
IN
of
Congestive heart failure (HF) in rats was produced by repeated injections (6 x 2.5 mg/kg, i.p., over 2 weeks) of adriamycin (ADR) - an effective antitumor antibiotic. Several hemodynamic and morphological characteristics in this HF were found to be in common with those seen in cancer patients treated with anthracyclines. The HF is likely mediated by increased oxidative stress, Pre- and concurrent-treatment of the animals with probucol (12 x 10 mg/kg), a lipid-lowering drug and an antioxidant, against ADR-induced offered complete protection cardiomyopathic changes with a significant normalization of the oxidative stress. Probable contribution of lipidlowering properties of probucol in preventing HF was also studied by comparing its effect with that of lovastatin another lipid-lowering drug. Experiments to examine the effects of probucol on antitumor properties of ADR revealed that the proposed combination did not compromise antitumor efficacy of the drug. Thus, the combination therapy using ADR and probucol has a great potential for clinical application. The study also showed that increased oxidative stress and reduced antioxidant reserve contribute in the pathogenesis of HF.
Since strain induced a sustained elevated level in intracellular reactive oxygen species (ROS), we hypothesised that the ROS could be a modulator in cyclic strain-induced endothelin- 1 (Et- 1) gene expression in endothelial cells. Cultured endothelial cells grown on a flexible membrane base were deformed by vacuum to 25% of maximum strain at 60 cycles/min for various periods. Human umbilical vein endothelial cells (HUVEC) subjected to strain showed increased Et-l secretion and intracellular Et-l mRNA level compared with unstrain control cells. Pretreated HLJVEC with antioxidant, catalase (300 U/ml) or 1,3-Dimethyl-2-Thiourea (DMTU; 0.1 mM), abolished the strain-induced Et-l release and intracellular Et-l mRNA level. When transfected the fusion plasmids containing Et-l 5 ’-flanking sequence (4.4 kb) and the chloramphenicol acetyltransferase gene into bovine aortic endothelial cells, cells strained for 6 hours allowed maximal transcription, whereas pretreatment with catalase also decreased Et-l promoter activity. These data indicate that ROS involved in cyclic strain-induced Et-l gene expression in endothelial cells.
(Supported by the Manitoba Heart and Stroke Foundation.)
THE STATE OF PROCESSES OF LIPID PEROXIDATION AND HEMOSTASIS IN PLAGUE INTOXICATION N.Chesnokova, G.Afanasieva, E.Ponukalina Medical Universiw, Saratov, Russia
GENE EXPRESSION AND ATHEROSCLEROSIS S. YlCHerttuala A. I. Virtanen Institute, University of Kuopio, Finland Oxidative modification of low density lipoprotein (LDL) plays an important role in atherogenesis. Oxidized LDL has several effects on gene expression on the arterial wall cells. In vitro, minimally oxidized LDL is a potent inducer of monocyte chemotactic protein-l stimulating factor-l colony (MCP-I), macrophage (MCSF-1) and tissue factor (TF). If formed under endothelium, minimally oxidized LDL can stimulate monocyte binding to endothelium, monocyte influx into the artery wall and thrombogenic properties of endothelium. When LDL is oxidized more extensively it becomes cytotoxic to arterial wall cells. Extensively oxidized LDL could lead to a dysfunction and/or injury of endothelial cells. Extensively oxidized LDL also affects plateletderived growth factor (PDGF) expression by arterial wall cells and inhibits endothelial cell-derived relaxing factor (EDRF) activity. In summary: When LDL is oxidized it aquires several atherogenic properties which can influence cellular lipid metabolism and various other functions of the arterial cells. The identification of LDL oxidation as one of the key events in the pathogenesis of atherosclerosis offers an interesting possibility to reduce atherosclerosis by antioxidants and other compounds that protect LDL against oxidative damage.
In experiments on white rats in plague intoxication produced by intraabdominal administration of vaccine strain EB, we observed the accumulation of lipid hydroperoxides and malonic dialdehyde in blood plasma, erythrocytes and some inner organs, the decrease of the level of sulfhydryl groups of thiol combinations in blood serum despite the increase in the activity of blood superoxide dismutase and catalase. At the same time we noted hypercoagulation shears in the early stage of intoxication to be replaced in succession by hypocoagulative disorders in the background of stable activation of anticoagulant mechanisms and tibrinolysis system. A definite correction of hemostasis disorders and lipid peroxidation process is achieved when using antihypoxants.
17