Doxorubicin is an effective chemotherapeutic agent used to treat
malignancies, but it causes
cardiomyopathy. Preliminary evidence suggests that
desacyl ghrelin might have protective effects on
doxorubicin cardiotoxicity. This study examined the cellular effects of
desacyl ghrelin on myocardial
fibrosis and apoptosis in a
doxorubicin cardiomyopathy experimental model. Adult C57BL/6 mice received an
intraperitoneal injection of
doxorubicin to induce
cardiomyopathy, followed by 4-day treatment of saline (control) or
desacyl ghrelin with or without [d-Lys3]-GHRP-6 (a
growth hormone secretagogue receptor or GHSR1a antagonist). Ventricular structural and functional parameters were evaluated by transthoracic echocardiography. Molecular and cellular measurements were performed in ventricular muscle to examine myocardial
fibrosis and apoptosis. Cardiac dysfunction was induced by
doxorubicin, as indicated by significant decreases in ventricular fractional shortening and ejection fraction. This
doxorubicin-induced cardiac dysfunction was prevented by the treatment of
desacyl ghrelin no matter with or without the presence of [d-Lys3]-GHRP-6.
Doxorubicin induced
fibrosis (accumulated
collagen deposition and increased CTGF), activated apoptosis (increased TUNEL index, apoptotic DNA fragmentation, and
caspase-3 activity and decreased Bcl-2/Bax ratio), and suppressed phosphorylation status of prosurvival signals (ERK1/2 and Akt) in ventricular muscles. All these molecular and cellular alterations induced by
doxorubicin were not found in the animals treated with
desacyl ghrelin. Notably, the changes in the major markers of apoptosis,
fibrosis, and Akt phosphorylation were found to be similar in the animals following the treatment of
desacyl ghrelin with and without GHSR antagonist [d-Lys3]-GHRP-6. These findings demonstrate clearly that
desacyl ghrelin protects the cardiomyocytes against the
doxorubicin-induced
cardiomyopathy by preventing the activation of cardiac
fibrosis and apoptosis, and the effects are probably mediated through GHSR-independent mechanism.