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Theses

Cardioprotection à la phase aiguë de l'infarctus

Abstract : Prompt reperfusion remains the mainstay strategy for reducing myocardial infarct size and improving outcomes. Paradoxically, reperfusion itself may induce myocardial damage termed, reperfusion injury. Improvements in morbidity and mortality would not be achieved by reperfusion without new adjunctive therapies. Although ischemic postconditionning (IPost, brief intermittent periods of ischemia and reflow applied at the onset of reperfusion following sustained ischemia) has been successful in attenuating infarct size in all species including humans, its use is limited to patients with ongoing acute myocardial infarction subjected to coronary angioplasty. IPost has been shown to exert its cardioprotective effect by upregulating prosurvival kinases named RISK (consisting of PI3K/Akt and ERK1/2) and the downstream target GSK-3β. 1) First, we thought to compare the cardioprotective effect of IPost and a pharmacological cardioprotective agent (erythropoietin, EPO), known to activate the same signalling pathways. In our model, EPO showed a trend for better protective effects than IPost through higher phosphorylation levels of ERK1/2 and GSK-3β. 2) Second, we examined whether EPO-induced cardioprotection is maintained in presence of type I diabetes and insulin resistance syndrome. Diabetic rat hearts were refractory to EPO-induced cardioprotection with altered components of RISK signalling pathway that inhibit GSK-3β. Moreover, this lack of cardioprotection was not dose-related, since higher EPO doses did not restore the cardioprotective effects. Interestingly, direct inhibition of GSK-3β may provide an alternative therapeutic option to reduce infarct size in presence of diabetes. On the other hand, the cardioprotective effect of EPO was maintained in our model of insulin resistance syndrome. 3) In the third part of this work we thought to examine the mechanism involved in remote postconditionning (RIPost)-induced cardioprotection. RIPost, a non-invasive application of brief ischemia in remote organs just before myocardial reperfusion, is a novel approach to attenuate reperfusion injury. In our model, RIPost was as effective as local IPost to prevent reperfusion injury with trend superiority to RIPost. Similarly to IPost, RIPost activated RISK pathway. GSK-3β would be implicated in RIPost-induced cardioprotection.
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Submitted on : Monday, April 18, 2011 - 11:17:35 AM
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  • HAL Id : tel-00586689, version 1

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Nehmat Ghaboura. Cardioprotection à la phase aiguë de l'infarctus. Médicaments. Université d'Angers, 2010. Français. ⟨tel-00586689⟩

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