title: Cardiac systolic dysfunction in doxorubicin-challenged rats is associated with upregulation of MuRF2 and MuRF3 E3 ligases.
abstract: Doxorubicin (DOXO) is an efficient and low-cost chemotherapeutic agent. The use of DOXO is limited by its side effects, including cardiotoxicity, that may progress to cardiac failure as a result of multifactorial events that have not yet been fully elucidated. In the present study, the effects of DOXO at two different doses were analyzed to identify early functional and molecular markers of cardiac distress. One group of rats received 7.5 mg/kg of DOXO (low-dose group) and was followed for 20 weeks. A subset of these animals was then subjected to an additional cycle of DOXO treatment, generating a cumulative dose of 20 mg/kg (high-dose group). Physiological and biochemical parameters were assessed in both treatment groups and in a control group that received saline. Systolic dysfunction was observed only in the high-dose group. Mitochondrial function analysis showed a clear reduction in oxidative cellular respiration for animals in both DOXO treatment groups, with evidence of complex I damage being observed. Transcriptional analysis by quantitative polymerase chain reaction revealed an increase in atrial natriuretic peptide transcript in the high-dose group, which is consistent with cardiac failure. Analysis of transcription levels of key components of the cardiac ubiquitin-proteasome system found that the ubiquitin E3 ligase muscle ring finger 1 (MuRF1) was upregulated in both the low- and high-dose DOXO groups. MuRF2 and MuRF3 were also upregulated in the high-dose group but not in the low-dose group. This molecular profile may be useful as an early physiological and energetic cardiac failure indicator for testing therapeutic interventions in animal models.
authors.affiliation: Programa de Biologia Molecular e Estrutural, Instituto de Biofísica Carlos Chagas Filho; ; Programa de Biologia Molecular e Biotecnologia, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro; ; Ecodata Exames Médicos Ltda; ; Instituto Nacional para Pesquisa Translacional em Saúde e Ambiente na Região Amazônica, Conselho Nacional de Desenvolvimento Científico e Tecnológico/MCT;
authors.forename: Marcia Gracindo
authors.initials: MG
authors.lastname: da Silva
authors.forename: Elisabete
authors.initials: E
authors.lastname: Mattos
authors.forename: Juliana
authors.initials: J
authors.lastname: Camacho-Pereira
authors.forename: Tatiana
authors.initials: T
authors.lastname: Domitrovic
authors.forename: Antonio
authors.initials: A
authors.lastname: Galina
authors.forename: Mauro W
authors.initials: MW
authors.lastname: Costa
authors.forename: Eleonora
authors.initials: E
authors.lastname: Kurtenbach
keywords: Cardiomyopathy; Doxorubicin; Echocardiography; Gene expression; Respirometry; Ubiquitin-proteasome system