Role of the phosphoinositide-3-kinase/serin-treonin kinase (PI3K/AKT) signaling pathway in the expression of dystrophin in the myocardium of animals submitted to cecal ligation and puncture (CLP)

Abstract

Sepsis is considered the most important cause of morbidity and mortality in intensive care units and can be defined as consensus conference as "the systemic inflammatory response syndrome (SIRS) that occurs during infection" usually aggravated by multiple physiological and immunological abnormalities, which can progress to septic shock, multiple organ failure and death. Excessive production of inflammatory mediators associated with activation of inflammatory cells causes hemodynamic changes, characterized by disturbances of the microcirculation and cellular alterations that cause the imbalance between blood flow and tissue metabolic requirements, and the heart is considered the main target in sepsis. Cardiac dysfunction in sepsis may be explained by several mechanisms such as changes in blood volume, reduced activation of beta-adrenergic receptors, depression of signaling pathways post-receptor, damage to the electromechanical coupling of cardiac cells and decreased sensitivity to calcium level at myofibrils. Whereas the precise mechanisms by which stress-induced sepsis modulates the response of the cardiac cell is an issue to be elucidated, there are currently studies the role of proposing a variety of signaling pathways may be activated during sepsis and contribute to the occurrence of cardiac dysfunction. Considering these signaling pathways are involved in the inflammatory response modulation and could contribute to cardiac dysfunction induced by sepsis we emphasize the phosphoinositide-3-kinase/serin-treonin kinase (PI3K/AKT) signaling pathway. PI3Ks are the enzymes responsible for intracellular signal transduction, regulation of cell proliferation and migration, cell survival, inflammatory response, gene expression, cellular metabolism, cytoskeletal rearrangements and the calcium flow. The cell signaling pathways related to PI3K play an important role in the pathogenesis of diseases with inflammatory component, such as cancer, myocardial infarction, atherosclerosis, ischemia-reperfusion injury and sepsis. Recent evidence indicates that the PI3K/AKT signaling pathway may represent a compensatory mechanism in order to limit the pro-apoptotic and pro-inflammatory events in response to sepsis. This pathway has also been reported as a regulator of cardiomyocyte contractility, which could be related to expression of the glycoproteins dystrophin (CDG). According to the above, the objectives of this project: (a) to evaluate the involvement of the PI3K/AKT signaling pathway in cardiac alterations in sepsis induced by cecal ligation and puncture in WT and PI3K-deficient (knockout - /-PI3K), (b) to evaluate the possible relation between PI3K/AKT activation and the dystrophin expression in the myocardium of septic animals, c) to evaluate, through in vitro studies, the role the PI3K/AKT pathway using the specific blocker LY294002, which is crucial for studies of cellular processes that involve this pathway, in cultured H9c2 cells stimulated with serum from control and septic animals, and d) to evaluate the cardiac function in vivo using echocardiography. (AU)