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The main goal of the study was to determine whether hypoxia augments the toxicity of anticancer drugs towards cardiomyocytes. Drugs selected for this experiment were those that disturb the cardiac redox equilibrium. Cardiomyocytes were incubated for 24 h with doxorubicin, tirapazamine, and 5-fluorouracil, each at three doses, under normoxia and under 50% and 90% hypoxia. The cytotoxic effect was evaluated on the basis of the percentage of living cells, cell vitality (assessed by the MTT assay), and morphology. In addition, the oxidative marker and pH value were determined. Varied protective effects of hypoxia on cell morphology were observed in all cases except the medium concentration of tirapazamine. The 50% hypoxia prevented the toxic effects of all tested drugs. The 90% hypoxia, on the other hand, was effective against the cytotoxic action of doxorubicin and 5-fluoruracil, but the cytotoxicity of tirapazamine increased. It was found that under the 90% hypoxia the oxidative stress observed under normoxia and the 50% hypoxia was greatly reduced. The study revealed that the above drugs did not activate anaerobic glycolysis.
Rapid resynthesis of the adenylate pool in cardiac myocytes is important for recovery of contractility and normal function of regulatory mechanisms in the heart. Adenosine and adenine are thought to be the most effective substrates for nucleotide synthesis, but the possibility of using other compounds has been studied very little in cardiomyocytes. In the present study, the effect of S-adenosyl-L-methionine (SAM) on the adenylate pool of isolated cardiomyocytes was investigated and compared to the effect of adenine and adenosine. Adult rat cardiomyocytes were isolated using the collagenase perfusion technique. The cells were incubated in the presence of adenine derivatives for 90 min followed by nucleotide determination by HPLC. The concentrations of adenine nucleotides expressed in nmol/mg of cell protein were initially 22.1 ± 1.4, 4.0 ± 0.3 and 0.70 ± 0.08 for ATP, ADP and AMP, respectively (n = 10, ± S.E.M.), and the total adenylate pool was 26.8 ± 1.6. In the presence of 1.25 mM SAM in the medium, the adenylate pool increased by 5.2 ± 0.4 nmol/mg of cell protein, but only if 1 mM ribose was additionally present in the medium. No changes were observed with SAM alone. A similar increase (by 4.9 ± 0.6 nmol/mg protein) was observed after incubation with 1.25 mM adenine plus 1 mM ribose, but no increase was observed if ribose was omitted. Adenosine at 0.1 or 1.25 mM concentrations also caused an increase in the adenylate pool (by 5.2 ± 1.0 and 5.2 ± 0.9 nmol/mg protein, respectively), which in contrast to the SAM or adenine was independent of the additional presence of ribose. Thus, S-adenosyl-L-methionine could be used as a precursor of the adenylate pool in cardiomyocytes, which is as efficient in increasing the adenylate pool after 90 min of incubation as adenosine or adenine. Nucleotide synthesis from SAM involves the formation of adenine as an intermediate with its subsequent incorporation by adenine phosphoribosyltransferase
We investigated the effect of 2-methyl-1,4-naphtoquinone (Menadione) on sarcoplasmic reticulum (SR) Ca2²⁺ content and electrically stimulated contractions (ESCs) of single isolated myocytes of guinea-pig ventricular myocardium. The contractures initiated by means of microinjections of caffeine into the close vicinity of the cell were used as an indirect index of the SR Ca²⁺ content. Superfusion of the cells for 45 min with Menadione resulted in gradual disappearance of contractile respones to caffeine, prolongation of time to peak amplitude of ESCs by 48±15% and complete inhibition of postrest and postextrasystolic potentiation. These results are consistent with those of Floreani and Caipenedo (7) who found that Menadione strongly inhibits the SR Ca²⁺ ATPase. Despite depletion of the SR Ca²⁺ the amplitude of ESCs did not change which suggests that contractions were initiated in the cells treated with Menadione by Ca²⁺ derived from the sources other than the SR.
 It is well known that 5-lipoxygenase derivates of arachidonic acid play an important pathogenic role during myocardial infarction. Therefore, the gene encoding arachidonate 5-lipoxygenase (ALOX5) appears to be an attractive target for RNA interference (RNAi) application. In experiments on cultivated cardiomyocytes with anoxia-reoxygenation (AR) and in vivo using rat model of heart ischemia-reperfusion (IR) we determined influence of ALOX5 silencing on myocardial cell death. ALOX5 silencing was quantified using real-time PCR, semi-quantitative PCR, and evaluation of LTC4 concentration in cardiac tissue. A 4.7-fold decrease of ALOX5 expression (P < 0.05) was observed in isolated cardiomyocytes together with a reduced number of necrotic cardiomyocytes (P < 0.05), increased number live (P < 0.05) and unchanged number of apoptotic cells during AR of cardiomyocytes. Downregulation of ALOX5 expression in myocardial tissue by 19% (P < 0.05) resulted in a 3.8-fold reduction of infarct size in an open chest rat model of heart IR (P < 0.05). Thus, RNAi targeting of ALOX5 protects heart cells against IR injury both in culture and in vivo.
Peroxisome proliferator-activated receptor alpha (PPAR) plays a crucial role in the transcriptional regulation of myocardial lipid metabolism. In vitro studies on isolated cardiomyocytes showed that PPAR activation induces expression of numerous genes involved in virtually all steps of fatty acid catabolism. However, there is very few data on the effect of PPAR activation on the content and composition of myocardial lipids in vivo. Therefore, our main aim was to examine effects of selective PPAR agonist WY-14643 on the content and fatty acid composition of major lipid classes in the heart of rats fed a standard chow (STD) or a high-fat diet (HFD). In STD rats WY-14643 paradoxically decreased palmitate oxidation rate in the heart, however, in HFD animals such effect was not observed. WY-14643 markedly reduced myocardial free fatty acid and diacylglycerol content in STD rats, whereas in HFD group the opposite effect was observed. These changes reflected alterations in plasma lipid concentration which suggests that effects of WY-14643 on the heart were indirect and secondary to changes in plasma lipid availability induced by the drug. Basal myocardial glucose uptake was not affected by PPAR agonist in either group, however, glycogen content in the heart was markedly increased. WY-14643 exerted profound influence on the fatty acid composition of myocardial phospholipids in both diet groups. These changes included increased percentage of monounsaturated fatty acids and replacement of n-3 polyunsaturated fatty acids (PUFA) by those from the n-6 family. This action of WY-14643 might be detrimental to the heart since n-3 PUFA possess cardioprotective and antiarrhythmic properties.
Protection from doxorubicin-induced lipid peroxidation in vivo by two pyrroline and pyrrolidine nitroxides, Pirolin, PL, and Pirolid, PD, was examined in the heart tissue of rats treated with this drug. The level of lipid peroxidation was estimated on the basis of MDA content. A considerable (threefold) increase in the MDA amount was found in heart homogenates from rats injected with doxorubicin, whereas no significant changes in MDA content compared to control were observed in cardiomyocytes treated with the nitroxides (Pirolin or Pirolid) only. Pirolin injected simultaneously with doxorubicin showed antioxidative effect and markedly attenuated lipid peroxidation in the heart tissue caused by this drug. In contrast to Pirolin, structurally related Pirolid was ineffective in the protection of heart myocytes from DOX-induced lipid peroxidation.
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