(P179) STIMULATING THE RETINOIC ACID BETA2 RECEPTOR ATTENUATES DOXORUBICIN-INDUCED ACUTE HEART FAILURE BY REDUCING THE PRO-FIBROTIC RESPONSE.

Background: Doxorubicin (DOXO) is widely used as an anticancer drug, but it also induces cardiomyopathy and heart failure. We have recently reported that pharmacologically stimulating the retinoic acid Beta2-receptor (RARB2) mitigates oxidative stress and fibrosis after myocardial infarction. On these grounds, we hypothesized that RARB2 stimulation could rescue and/or prevent cardiac dysfunction and cardiac fibrosis and increase survival in a murine model of DOXO-induced acute heart failure.

METHODS AND RESULTS: We performed in vivo experiments to assess the effects of RARB2 stimulation on cardiac function, survival and cardiac interstitial fibrosis in murine models of DOXO-induced heart failure. Mice were treated with a single dose of DOXO (20 mg/kg; i.p. injection), and then received RARB2 stimulation in 4 doses of 20 mg/kg on day 2, 3, 4, 5 (rescue protocol). In the prevention protocol, mice received RARB2 stimulation in 2 doses (12 mg/kg) on days 1 and 2, followed by one i.p. injection of 20 mg/kg DOXO on day 3. Echocardiography was performed to assess cardiac function. Cardiac fibrosis was evaluated by Masson’s and Picrosirius red staining.

RARB2 stimulation significantly attenuated the progressive decrease in left ventricle ejection fraction and markedly reduced cardiac fibrosis after DOXO treatment. We also observed that RARB2 stimulation improved survival.

Conclusion: Taken together, our data indicate that RARB2 stimulation ameliorates cardiac function, decreases fibrosis, and improves survival in a murine model of acute DOXO cardiotoxicity.