Mechanisms of cell death in doxorrubicin induced cardiotoxicity

• Grant number: 12/17280-3
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2013
• End date: August 31, 2015
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Ana Lucia do Anjos Ferreira
• Grantee: Ana Lucia do Anjos Ferreira
• Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated researchers: Daisy Maria Favero Salvadori ; Glenda Nicioli da Silva

Abstract

Cardiotoxicity induced by doxorubicin (DXR), an anthracycline isolated from Streptomyces peucetius, is one of the main secondary pathophisiological events that related to this antineoplasic compound. Cell death resulting from the toxic conditions is associated to deregulated metabolic mechanisms. Intracellular calcium flux and mitochondrial permeability seem to be important factors that lead to cell death. Reactive oxygen species can form aldehydes on the cells membranes, which alter the mitochondrial redox state and form adducts with proteins, inhibiting their activities. However, there is a specific class of enzymes, the aldehydes dehydrogenases (ALDH2), which removes the aldehydes from the cells and reduces their deleterious effects. The present study aims to evaluate the mechanism of cardiotoxicity induced by doxorrubicin and also the cardioprotective potential of the ALDH2 gene. We will evaluate: the expression of genes related to polyunsaturated fatty acid oxidation by PCR arrays and to calcium channels (PPI and C1QBP) and to cell death (Bax and Bcl2) by qPCR-RT; mitochondrial and citoplasmatic levels of cacium; apoptosis and necrosis rates by flow cytometry; activity of ALDH2 gene and its respective enzyme and microRNAS associated with ALDH2 regulation. Cardiac lipid peroxidation also will be determined. We expect that the set of results may contribute to the elucidation of the cardiotoxic potential of doxorrubicin and also for efficient strategies to reduce the side effects of DXR on the heart. (AU)