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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)

Grant number: 11/23220-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2012
Effective date (End): January 31, 2014
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Simone Gusmão Ramos
Grantee:Erica Carolina Campos Pulici
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Sepsis is considered the most important cause of morbidity and mortality in intensive care units and can be defined as a complex clinical syndrome of severe systemic inflammatory response (SIRS) with multiple physiological and immunological abnormalities, commonly associated with bacterial or fungal infections, which can progress to septic shock, multiple organ failure and death. Excessive production of inflammatory mediators associated with excessive activation of inflammatory cells causes circulatory and hemodynamic changes related to the pathogenesis of sepsis, characterized by microcirculatory disturbances and cellular changes that cause an imbalance between blood flow and tissue metabolic requirements, resulting in failure of multiple organs. Cardiac dysfunction in sepsis may be explained by several mechanisms such as alterations 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 in myofibrilar level. Taking into account that the precise mechanisms by which stress modulates the cardiac cells response to sepsis is a question to be elucidated, there are currently studies suggests that the role of a variety of signaling pathways that may be activated during sepsis and contribute to cardiac dysfunction. Among these signaling pathways involved in the modulation of inflammatory response and could contribute to cardiac dysfunction induced by sepsis, the signaling pathway of phosphatidylinositol-3-kinase/serin-treonin kinase (PI3K/AKT) is emphasized. The PI3Ks are enzymes responsible for intracellular signal transduction, responsible to proliferation and cell migration, cell survival, inflammatory response, gene expression, cellular metabolism, and cytoskeletal rearrangements and calcium influx. 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 septic stimuli. This pathway was also reported as direct regulator of cardiomyocyte contractility, which could be related to the expression of the dystrophin and associated glycoproteins (DGC). According to the above, the purposes of this project are: (a) to analyze the involvement of the PI3K/AKT signaling pathway in cardiac changes in experimentally induced septic cardiomyopathy by cecal ligation and puncture in WT mice and PI3K-deficient mice (knockout - /-PI3K), (b) to analyze the possible relation between the activation of the PI3K/AKT and the expression of dystrophin in the myocardium of septic animals in the evolution of myocardial injury induced by sepsis, c) to analyze, 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 H9c2 cultured cells stimulated with serum from control and septic animals, and d) to evaluate the cardiac function in vivo through echocardiography. This project could provide a highly significant benefit in this specific area of knowledge, particularly the role of PI3K/Akt signaling pathway and the dystrophin loss, providing a novel mechanism intrinsic of cardiac abnormalities induced by sepsis.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MACHADO, JULIANA REIS; SOAVE, DANILO FIGUEIREDO; DA SILVA, MARCOS VINICIUS; DE MENEZES, LILIANA BORGES; ETCHEBEHERE, RENATA MARGARIDA; GONCALVES DOS REIS MONTEIRO, MARIA LUIZA; DOS REIS, MARLENE ANTONIA; MIRANDA CORREA, ROSANA ROSA; NUNES CELES, MARA RUBIA. Neonatal Sepsis and Inflammatory Mediators. Mediators of Inflammation, 2014. Web of Science Citations: 37.

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