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

AISICOVICH, MAIA; LANDA, MARÍA SILVINA; SCHUMAN, MARIANO LUIS; PIROLA, CARLOS JOSÉ; PERES DIAZ, LUDMILA SOLEDAD; TOBLLI, JORGE EDUARDO; GARCÍA, SILVIA INÉS

LIFE SCIENCES

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2020 vol. 261

0024-3205

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.