Role of netosis as modulator of doxorubicin-induced cardiotoxicity

Abstract

Doxorubicin is a chemotherapeutic used in the treatment of malignant neoplasms with high effectiveness. However, it may result in cardiotoxicity, which manifests as left ventricular dilatation and cardiac dysfunction. The pathophysiology of cardiotoxicity is not yet clearly understood, but mitochondrial dysfunction, increased oxidative stress and activation of matrix metalloproteinases (MMP) occur. Among the several multifactorial pathways that are activated after administration of doxorubicin, the inflammatory response is an important modulator of the cardiotoxicity process. In this context, the role of neutrophils deserves special mention, since they are the first cells to respond to tissue injury. Thus, through the production of chemoattractant substances, they are able to "orchestrate" the entire subsequent immune response, which is certainly related to the installation of cardiotoxicity. In addition to phagocytosis and degranulation, neutrophils are able to produce NETs (neutrophill extracellular traps), in a process called netosis. NETs are network structures composed of cytoplasmic and nuclear material such as DNA, myeloperoxidase and elastase. Extrusion of NETs occurs in a coordinated manner early in response to various infectious stimuli or not. To date, there are no data in the literature regarding the influence of NETs on doxorubicin-induced cardiotoxicity. In this sense, the first objective of this project will be to identify potential similarities and differences between the acute and chronic symptoms of cardiotoxicity induced by doxorubicin. Additionally, we will analyze whether the toxicity resulting from acute and chronic doxorubicin is associated with the presence of NETs and whether there is an association of netosis with inflammatory variables, cardiac energy metabolism, oxidative stress and cardiac extracellular matrix. Finally, we intend to establish a cause / consequence relationship between netosis and cardiac changes induced by doxorubicin. (AU)