PI3Kgama regula gp91phox (NOX-2) e induz alterações cardiodeletérias

Abstract

Cardiac remodeling characterizes a group of molecular, cellular and tissue changes that reflect the structural and/or functional alterations of the heart in response to different stimuli, which can be physiological or pathological. Several physiological systems play essential roles for the establishment and progression of these changes. Among them, the renin-angiotensin-aldosterone and the autonomic nervous system are fundamental in the physiological adjustments of cardiac frequency, strength and hemodynamics. On the other hand, the excessive action of the effectors of these systems can generate pathological changes in the heart muscle, which, when unresolved, are associated with the onset of heart disease. Pathological cardiac remodeling can be characterized by hypertrophy, fibrosis, and inflammation, which are, at least in part, mediated by the imbalance between reactive oxygen species (ROS) production and antioxidant defenses, which is defined as oxidative stress. In this context, gp91phox (NOX-2) is a key agent, as it is the main source of ROS in the cardiac tissue. The activity of gp91phox can be modulated by different stimuli, and phosphoinositide-3-kinases (PI3K), a family of kinase that regulate functions such as cardiomyocyte growth, survival, inflammation and cardiac contractility, are also known to be associated with the activity of gp91phox in ROS production. Although there is sparse evidence that gp91phox mediates the rapid cardiac effects of aldosterone and that both PI3K and gp91phox are involved with the cardiodeleterious effects of chronic adrenergic stress, mechanistic data on how this pathway is activated has not yet been consolidated. Therefore, the aim of this work is to understand the role of gp91phox in acute and chronic cardiac alterations that depend on oxidative stress induced by different stimuli, and to define the involvement of PI3K in this process. In the present study, we evaluated the role of gp91phox (i) in acute cardiac changes induced by aldosterone, and (ii) in cardiac remodeling induced by chronic adrenergic stress. In the first chapter, our results show that gp91phox mediates the acute effects of aldosterone: (a) on ROS production and protein carbonylation in cardiac tissue; (b) in the oxidation of calmodulin kinase II (CaMKII) and in the cytoplasmic calcium transient; and (c) in cellular and tissue proinflammatory pathways in the heart. We also show that PI3Kγ participates in the oxidative effect of aldosterone on isolated ventricular cardiomyocytes. In the second chapter, we show that: (d) that NADPH oxidase participates in the fibrotic and hypertrophic effects of chronic adrenergic stress; and that (e) these effects depend on the gp91phox/PI3Kγ/ROS pathway. Together, these evidences bring a greater understanding of the involvement of gp91phox in acute and chronic cardiac abnormalities that depend on oxidative stress, and the crucial role of PI3Kγ as its upstream mediator. Our data support the idea that tools targeting the PI3Kγ/gp91phox/ROS signaling pathway may be important in the study of the mechanisms of cardiac diseases characterized by inflammation, hypertrophy and cardiac fibrosis.