Ghrelin Ameliorates Doxorubicin‐induced Cardiomyopathy and Cardiac Fibrosis

Abstract

Doxorubicin (DOX)‐induced cardiac toxicity is a serious clinical concern. This study aimed to examine the effects of ghrelin, a natural brain‐gut peptide, on DOX‐induced cardiomyopathy and cardiac fibrosis. We tested the hypothesis that ghrelin can alleviate cardiomyopathy and cardiac fibrosis induced by DOX. Adult C57BL/6 mice were randomly assigned to Control, DOX, and DOX with ghrelin treatment groups. Mice in Control and DOX groups were exposed to a single i.p. injection of saline and 15 mg/kg of DOX, respectively. Twelve hours after DOX injection, mice in DOX with ghrelin treatment group were i.p. injected with 100 μg/kg of unacylated ghrelin twice a day for 4 days. Echocardiography was used to examine cardiac function. Mice were sacrificed and the left ventricle (LV) was used to examine cardiac fibrosis by Masson trichrome stain. RT‐PCR was used to examine the expression of fibrosis‐associated genes. According to our echocardiographic examination, DOX induced a decrease in LV fractional shortening and ejection fraction by 20% and 9%, respectively (p<0.01). Conversely, the DOX‐induced decrease in fractional shortening and ejection fraction were not found in mice treated with ghrelin. Our staining analysis indicated that the amount of cardiac fibrotic tissue was increased by DOX whereas ghrelin treatment prevented the DOX‐induced increase in cardiac fibrosis. CTGF mRNA content and the ratio of CTGF/BNP mRNA were increased by 520% and 121%, respectively, in ventricular muscle of DOX group when compared to Control group (p<0.01). In contrast, CTGF mRNA and the ratio of CTGF/BNP mRNA were reduced by 68% and 44%, respectively, in DOX with ghrelin treatment group when compared to DOX group (p<0.05). The mRNA contents of BNP, TGF‐beta and PAI‐1 were not significantly changed in all groups. Our data demonstrate that ghrelin attenuates the DOX‐induced ventricular dysfunction and cardiac fibrosis. These findings suggest that ghrelin might be a potential target for developing treatment for DOX‐induced cardiotoxicity.