Acute myocardial infarction, characterized by myocardial damage due to ischemia- reperfusion events, is an important public health problem, being considered the main cause of morbidity and mortality worldwide. We have recently reported that ischemic preconditioning, characterized by brief insults of ischemia alternating with short periods of reperfusion, can produce cardioprotection against sustained ischemia. Moreover, we found that this process is dependent on the mitochondrial translocation of epsilon of protein kinase C isoform and subsequent phosphorylation of the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2), whose activation has an inverse correlation with the degree of myocardial infarction after cardiac ischemia/reperfusion. Similar to preconditioning, prior exercise is also able to protect the heart against ischemia/reperfusion injury; however, the cellular aspects involved in this process are still unclear need to be better described. Our hypothesis is that exercise-mediated activation of intracellular axis PKCepsilon-ALDH2 is crucial to induces cardioprotection. To test this hypothesis, C57BL6 male mice will be submitted to a protocol of aerobic exercise for seven days and afterwards exposed to a global ex vivo ischemia/reperfusion injury using the Langendorff apparatus (retrograde perfusion in ex vivo isolated heart). Subsequently we will evaluate myocardial infarct size, total and mitochondrial PK Cepsilon expression and ALDH2 activity, which is the main PK Cepsilon target during preconditioning-mediated cardioprotection. These measurements will be performed in control, ischemia/reperfusion and exercise+ischemia
/reperfusion groups. After validation the aforementioned hypothesis, we will evaluate the real contribution of this axis during exercise-mediated cardioprotection using pharmacological and genetic manipulations available in our laboratory which are able to activate and to inhibit either PK Cepsilon or ALDH2. Thus, the aim of the current proposal is to better understand the molecular aspects of exercise- mediated cardioprotection against ischemia/reperfusion injury in mice as well as the contribution of the intracellular axis PKCepsilon-ALDH2.
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