Desacyl ghrelin prevents doxorubicin-induced myocardial fibrosis and apoptosis via the GHSR-independent pathway

Xiao M. Pei, Yat Ming Yung, Shea Ping Yip, Tin Cheung Ying, Iris F. Benzie, Parco M. Siu

Research output: Journal article publicationJournal articleAcademic researchpeer-review

43 Citations (Scopus)

Abstract

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.
Original languageEnglish
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume306
Issue number3
DOIs
Publication statusPublished - 1 Feb 2014

Keywords

  • Adriamycin
  • Apoptosis
  • Cardiomyopathy
  • Chemotherapy
  • Fibrosis
  • Growth hormone secretagogue receptor
  • Unacylated ghrelin

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

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