Some Biochemical Aspects of the Protective Effect of Trimetazidine on Rat Cardiomyocytes During Hypoxia and Reoxygenation

Fantini, Elisabeth; Demaison, Luc; Sentex, Emmanuelle; Grynberg, Alain; Athias, Pierre

doi:10.1006/jmcc.1994.1116

Cited by 135 publications

(76 citation statements)

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“…In this experimental model, trimetazidine did not change ATP production, either during hypoxia or reoxygenation. This effect of trimetazidine was attributed by the authors not to its antioxidant properties, but to changes in lipid metabolism (Fantini et al, 1994). In other models of ischemia-reperfusion, it has been demonstrated that the impact of ischemia on the mitochondrial respiratory chain mainly occurs at the level of complex I (Veitch et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…This raises the hypothesis that trimetazidine acts on heart mitochondria, thus allowing a better use of the limited amount of O 2 available during ischemia, by mechanisms not yet fully understood, but which may involve a preferential use of glucose and/or a decrease in reactive oxygen species production (Maupoil et al, 1990). In ischemic hearts perfused with free fatty acids and trimetazidine, ATP levels have been shown to be preserved by some authors (Fantini et al, 1994) and decreased by others (Demaison et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia

Monteiro

Duarte²,

Gonçalves

et al. 2004

European Journal of Pharmacology

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Trimetazidine is an anti-ischemic drug whose cytoprotective mechanisms are not yet fully understood (but until now mainly related to the trimetazidine-induced bmetabolic shiftQ from lipid h-oxidation to glucose aerobic oxidation). We studied the effect of trimetazidine on the mitochondrial function of ischemic Wistar rat hearts perfused with glucose, using a model of ex-vivo perfusion (Langendorff system). We measured the electrical potential of the mitochondrial membrane, O 2 consumption by the respiratory chain, energy charges generated and the enzyme activities of the respiratory chain complexes. In this model, trimetazidine had a preferential action on the oxidative system (mainly on complex I), increasing its enzyme activity and decreasing O 2 consumption after phosphorylation; this could decrease oxygen free radical production and increase mitochondrial integrity, thus allowing the maintenance of the electrical potential. These results allow us to better understand the cytoprotective effects of trimetazidine in coronary artery disease. D

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia

Monteiro

Duarte²,

Gonçalves

et al. 2004

European Journal of Pharmacology

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“…These effects of insulin on glucose metabolism are particularly important because a significant amount of glucose-derived ATP is used for maintaining proper cardiac function. In addition, the stimulation of myocardial glucose utilization and subsequent decrease in fatty acid oxidation has been proven to be efficacious in reducing ischemic injury (7)(8)(9)(10)(11). Moreover, insulin-stimulated glucose utilization may be a central component of the beneficial effects of glucose-insulin-potassium therapy on the ischemic heart (12).…”

mentioning

confidence: 99%

Akt Activity Negatively Regulates Phosphorylation of AMP-activated Protein Kinase in the Heart

Kovacic

Soltys

Barr

et al. 2003

Journal of Biological Chemistry

366

287

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In the heart, insulin stimulates a variety of kinase cascades and controls glucose utilization. Because insulin is able to activate Akt and inactivate AMP-activated protein kinase (AMPK) in the heart, we hypothesized that Akt can regulate the activity of AMPK. To address the potential existence of this novel signaling pathway, we used a number of experimental protocols to activate Akt in cardiac myocytes and monitored the activation status of AMPK. Mouse hearts perfused in the presence of insulin demonstrated accelerated glycolysis and glucose oxidation rates as compared with non-insulin-perfused hearts. In addition, insulin caused an increase in Akt phosphorylation and a decrease in AMPK phosphorylation at its major regulatory site (threonine 172 of the ␣ catalytic subunit). Transgenic mice overexpressing a constitutively active mutant form of Akt1 displayed decreased phosphorylation of cardiac ␣-AMPK. Isolated neonatal cardiac myocytes infected with an adenovirus expressing constitutively active mutant forms of either Akt1 or Akt2 also suppressed AMPK phosphorylation. However, Akt-dependent depression of ␣-AMPK phosphorylation could be overcome in the presence of the AMPK activator, metformin, suggesting that an override mechanism exists that can restore AMPK activity. Taken together, this study suggests that there is crosstalk between the AMPK and Akt pathways and that Akt activation can lead to decreased AMPK activity. In addition, our data suggest that the ability of insulin to inhibit AMPK may be controlled via an Akt-mediated mechanism.The insulin signaling cascade is an important signaling pathway responsible for controlling substrate preference in the heart. Indeed, insulin has been shown to stimulate myocardial glucose uptake (1, 2) and accelerate glycolysis (2, 3) and glucose oxidation rates (2, 4) as well as promote glycogen synthesis (5, 6). These effects of insulin on glucose metabolism are particularly important because a significant amount of glucose-derived ATP is used for maintaining proper cardiac function. In addition, the stimulation of myocardial glucose utilization and subsequent decrease in fatty acid oxidation has been proven to be efficacious in reducing ischemic injury (7-11). Moreover, insulin-stimulated glucose utilization may be a central component of the beneficial effects of glucose-insulin-potassium therapy on the ischemic heart (12). Two kinases that can be regulated by insulin are Akt and AMPK. 1 Akt is a serine/threonine protein kinase that can be activated by insulin via a multistep pathway involving a phosphatidylinositol 3-kinase-dependent mechanism (see Ref. 13 for review). Once Akt is phosphorylated and activated, it can promote glucose uptake and subsequent metabolism via translocation of glucose transporter (GLUT) 4 to the plasma membrane (14 -18). In addition, the phosphorylation and inhibition of glycogen synthase kinase (GSK) 3 by Akt activates glycogen synthase and thereby promotes glycogen synthesis (19). Recent evidence in heart indicates that the presence of...

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“…This model has been a good tool to study related cardiovascular problems, for instance, experiments on arrhythmogenic drugs, ischemia, hypoxia etc. [23,24,25,26,27]. EP signals have a close correlation of the depolarization and repolarizing phase of the action potentials ( Figure 1a).…”

Section: Cardiac Cells Culturementioning

confidence: 85%

In vitroarrhythmia generation by mild hypothermia: a pitchfork bifurcation type process

Xu¹,

Jacquir²,

Laurent³

et al. 2015

Physiol. Meas.

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The neurological damage after cardiac arrest (CA) constitutes a big challenge of hospital discharge.The therapeutic hypothermia (34 • C − 32 • C) has shown its benefit to reduce cerebral oxygen demand and improve neurological outcomes after the cardiac arrest. However, it can have many adverse effects, The process of therapeutic hypothermia after cardiac arrest can be represented by a Pitchfork bifurcation type process, which could explain the different ratio of arrhythmia among the adverse effects after this therapy. This nonlinear dynamics suggests that a variable speed of cooling / rewarming, especially when passing 35 • C, would help to decrease the ratio of post-hypothermia arrhythmia and then improve the hospital output.

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Some Biochemical Aspects of the Protective Effect of Trimetazidine on Rat Cardiomyocytes During Hypoxia and Reoxygenation

Cited by 135 publications

References 0 publications

Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia

Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia

Akt Activity Negatively Regulates Phosphorylation of AMP-activated Protein Kinase in the Heart

In vitroarrhythmia generation by mild hypothermia: a pitchfork bifurcation type process

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