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Protection du myocarde ischémique et pore géant mitochondrial : applications pharmacologiques

Abstract : Ischemic coronary artery disease remains one of the main causes of mortality in the industrialized countries. The treatment of acute myocardial ischemia entered a new era where mortality can be reduced by 50% using revascularization procedures that allow a rapid return of blood flow to the ischemic area. However, this reperfusion leads to complications known as lethal reperfusion induced injury that have been described for the first time by Jennings et al., in 1960. It became crucial to develop cardioprotective strategies in combination with early reperfusion in order to improve myocardial function, to reduce the incidence of arrhythmias, to delay the onset of cardiomyocytes death and to limit the extension of infarct size following reperfusion. The discovery of two major forms of endogenous cardioprotective mechanisms, which consist of the realization of short cycles of ischemia/reperfusion (I/R) prior to a long period of ischemia (ischemic preconditioning) or before reperfusion after the long period of ischemia (Ischemic Postconditioning), encouraged the search for new pharmacological tools to protect the ischemic myocardium to develop our knowledge on the molecular mechanisms of lethal reperfusion injury and cell survival in the I/R process.The study of cell death mechanisms has highlighted the crucial role of the mitochondria and more specifically the increase in mitochondrial membrane permeability following I/R.One reason for increasing permeability is the formation/opening of a pore at mitochondrial membranes contact sites at reperfusion.This pore has been called "the mitochondrial permeability transition pore" (mPTP). Inhibition of this pore opening has been presented as a main strategy to protect the myocardium.Many studies have shown that reactive oxygen species (ROS) play a major role in I/R injury and mPTP opening, but there is very few information to date about the threshold and the period of ROS production (ischemia and/or reperfusion) that lead to mPTP opening.We designed a cellular model of hypoxia/reoxygenation (H/R) to establish a causal relationship between ROS production, mPTP opening and cell death while exploring the role of different types of ROS.This H/R model used freshly isolated adult rat cardiomyocytes and allowed us to measure online and simultaneously ROS production, mPTP opening and cell death. We have demonstrated that ROS production starts during the period of hypoxia and thisproduction is directly linked to the increase in the duration of hypoxia.This ROS production during hypoxia has been, for the first time, directly related to mPTP opening and cell death following H/R.We used this model to study the mechanism of action of two cardioprotective strategies, a new ligand of the mitochondrial translocator protein (TSPO), TRO 40303 and a RISK (Reperfusion Injury Salvage Kinase) pathway activator, morphine. We have shown that (1) the cardioprotective properties of TRO40303 were associated with inhibition of mPTP opening, a mechanism that could not be demonstrated using ex vivo experiments and (2) morphine that provoked infarct size limitation associated with an improvement of mitochondrial respiratory functions through RISK pathway activation, also inhibited mPTP opening and delayed cell death of isolated cardiomyocytes subjected to H/R.Finally, a question comes into sight whether the inhibition of oxidative stress may be a common mechanism to both cardioprotective pharmacological strategies that we have described using our H/R model. To do this, it would be possible to extend our model to genetically modified animals specifically adapted to understand the phenomena involved in antioxidant activity.On long-term, it will be necessary to develop our knowledge on ROS production during I/R by looking for the origin of this production, more precisely the role of the mitochondria and the effect of other reactive species in order to target the treatment and to develop new cardioprotective strategies.
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Rana Assaly. Protection du myocarde ischémique et pore géant mitochondrial : applications pharmacologiques. Médecine humaine et pathologie. Université Paris Sud - Paris XI, 2011. Français. ⟨NNT : 2011PA114820⟩. ⟨tel-00734466⟩

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