Early myocardial changes induced by doxorubicin in the nonfailing dilated ventricle

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Rodrigues, PG (Author) Other; Miranda Silva, D (Author) FMUP; Costa, SM (Author) Other; Barron, C (Author) Other; Hamdani, N (Author) Other; Moura C (Author) FMUP; Mendes, MJ (Author) Other; Sousa Mendes, C (Author) Other; Trindade, F (Author) Other; Fontoura, D (Author) Other; Vitorino, R (Author) FMUP; Linke, WA (Author) Other; Leite-Moreira AF (Author) FMUP; Falcao Pires, I (Author) FMUP

Journal

Title: American Journal of Physiology - Heart and Circulatory Physiology

Vol. 316

Pages: H459-H475

ISSN: 0363-6135

Publisher: American Physiological Society

Indexing

ISI Web of Knowledge - 16 Citations

Scopus - 20 Citations

Other information

Authenticus ID: P-00Q-79B

DOI: 10.1152/ajpheart.00401.2018

Abstract (EN): Several studies have demonstrated that administration of doxorubicin (DOXO) results in cardiotoxicity, which eventually progresses to dilated cardiomyopathy. The present work aimed to evaluate the early myocardial changes of DOXO-induced cardiotoxicity. Male New Zealand White rabbits were injected intravenously with DOXO twice weekly for 8 wk [DOXO-induced heart failure (DOXO-UF)] or with an equivolumetric dose of saline (control). Echocardiographic evaluation was performed, and myocardial samples were collected to evaluate myocardial cellular and molecular modifications. The DOXO-HF group presented cardiac hypertrophy and higher left ventricular cavity diameters, showing a dilated phenotype but preserved ejection fraction. Concerning cardiomyocyte function, the DOXO-HF group presented a trend toward increased active tension without significant differences in passive tension. The myocardial GSSG-to-GSH ratio and interstitial fibrosis were increased and Bax-to-Bcl-2 ratio presented a trend toward an increase. suggesting the activation of apoptosis signaling pathways. The macromolecule titin shifted toward the more compliant isoform (N2BA), whereas the stiffer one (N2B) was shown to be hypophosphorylated. Differential protein analysis from the aggregate-enriched fraction through gel liquid chromatography-tandem mass spectrometry revealed an increase in the histidine-rich glycoprotein fragment in DOXO-HF animals. This work describes novel and early myocardial effects of DOXO-induced cardiotoxicity. Thus, tracking these changes appears to be of extreme relevance for the early detection of cardiac damage (as soon as ventricular dilation becomes evident) before irreversible cardiac function deterioration occurs (reduced ejection fraction). Moreover, it allows for the adjustment of the therapeutic approach and thus the prevention of cardiomyopathy progression. NEW & NOTEWORTHY Identification of early myocardial effects of doxorubicin in the heart is essential to hinder the development of cardiac complications and adjust the therapeutic approach. This study describes doxorubicin-induced cellular and molecular modifications before the onset of dilated cardiomyopathy. Myocardial samples from doxorubicin-treated rabbits showed a tendency for higher cardiomyocyte active tension, titin isoform shift from N2B to N2BA, hypophosphorylation of N2B, increased apoptotic genes, left ventricular interstitial fibrosis, and increased aggregation of histidine-rich glycoprotein.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17