Short-term doxorubicin cardiotoxic effects: involvement of cardiac Thyrotropin Releasing Hormone system.

Abstract

Doxorubicin is an antineoplastic in the anthracycline class widely used for the treatment of several solid tumors and blood cancers. Cardiotoxicity is the major dose-limiting adverse effect of the drug. Chronic and accumulated doxorubicin administration cause myocyte damage and myocardial fibrosis. Doxorubicin-associated cardiotoxicity can be also observed after a short-course drug treatment even without clinical evidence of cardiac disease. Nevertheless, acute underlying mechanisms involved in the initiation of drug-induced cardiotoxicity remain poorly explored despite their similarities with pathophysiological conditions where cardiac TRH (cTRH) plays a central role. We showed that cTRH mediates myocardial injury induced by hypertension, and angiotensin II. Further, cTRH overexpression induces cardiac apoptosis, hypertrophy and fibrosis.

AIM:

To demonstrate that cTRH could mediate acute doxorubicin cardiotoxicity.

MAIN METHOD:

A single injection of doxorubicin (10 mg kg/day i.p.) was used to evaluate acute cardiac damage in a short-term experimental model of doxorubicin-induced cardiotoxicity. While inhibiting cTRH by small interfering RNA (siRNA), we evaluated the progression of cardiotoxicity.

KEY FINDINGS:

We found a doxorubicin-induced TRH overexpression in the LV, which was associated with apoptosis, hypertrophy and fibrosis. siRNA-mediated cTRH suppression prevented the doxorubicin-associated cardiac histological lesions.

SIGNIFICANCES:

doxorubicin requires an active cardiac TRH system to promote heart injury.

• Authors: Ludmila Soledad Peres Diaz, Mariano Luis Schuman, Maia Aisicovich, Jorge Eduardo Toblli, Carlos José Pirola, María Silvina Landa, Silvia Inés García
• Journal: Life sciences (Life Sci) Vol. 261 Pg. 118346 (Nov 15 2020) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 32853656 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• RNA, Small Interfering
• Thyrotropin-Releasing Hormone
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (toxicity)
• Apoptosis (drug effects)
• Cardiomegaly (chemically induced)
• Cardiotoxicity (etiology, physiopathology)
• Disease Progression
• Doxorubicin (toxicity)
• Fibrosis (chemically induced)
• Male
• Mice
• Mice, Inbred C57BL
• RNA, Small Interfering
• Thyrotropin-Releasing Hormone (genetics, metabolism)