In vitro cardiotoxicity induced by doxorubicin and cardioprotective potential of Alda-1

• Grant number: 17/03180-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: July 22, 2017
• End date: July 21, 2018
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Principal Investigator: Daisy Maria Favero Salvadori
• Grantee: Leonardo da Cunha Menezes Souza
• Supervisor: Yidong Bai
• Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Institution abroad: University of Texas Health Science Center at San Antonio (UTHSCSA), United States
• Associated to the scholarship: 14/09740-0 - Cardiotoxicity induced by doxorubicin in Wistar rats and the cardioprotective potential of Alda-1, BP.DR

Abstract

Cardiotoxicity induced by doxorubicin (DOX) is one of the main secondary pathophisiological events related to this antineoplasic compound, and the excessive reactive oxygen species (ROS) generation is a widely accepted mechanistic explanation. The chemical structure of DOX is particularly prone to undergo reversible reduction to semiquinone radicals, process that occurs predominantly in mitochondria and leads to ROS production. Therefore, it is not surprising that several mitochondrial alterations have been described, including loss of calcium loading capacity, mitochondrial DNA (mtDNA) damage and bioenergetic failure. Lipid peroxidation, induced by ROS, generates an array of primary lipid oxidation products, including 4-hydroxy-2-nonenal (4-HNE). 4-HNE is highly reactive and cytotoxic to all the major types of macromolecules and its increase has been associated with the DOX cardiotoxicity. The mitochondrial aldehyde dehydrogenase - ALDH2 - has rapidly emerged as a crucial enzyme involved in heart protection against oxidative stress, because of its ability to metabolize endogenous aldehydic products derived from lipid peroxidation, such as 4-HNE. However, in conditions of DOX-induced cardiotoxicity, ALDH2 can be inhibited by forming adducts with 4-HNE. Recently, a molecule able to increase ALDH2 activity was identified: Alda-1 or ALDH2 activator-1 has showed a cardioprotective potential under different conditions, but its mechanism of action is not completely known. Trying to contribute to minimize DOX cardiotoxicity and better understanding Alda-1 effectiveness, this study aims to evaluate the cardioprotective mechanisms of Alda-1 against DOX toxicity in cardiomyocytes of rats. Reactive oxygen species (ROS) generation, lipid peroxidation, mitochondrial membrane potential, mtDNA damage, ALDH2 enzyme activity and mitochondrial bioenergetics parameters will be assessed. It is expected that the dataset may contribute to new effective strategies for reducing the side effects of the antineoplastic drug doxorrubicin on the heart. (AU)