Protective effects of desacyl ghrelin on doxorubicin-induced and diabetic cardiomyopathy

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Protective effects of desacyl ghrelin on doxorubicin-induced and diabetic cardiomyopathy

 

Author: Pei, Xiao Meng
Title: Protective effects of desacyl ghrelin on doxorubicin-induced and diabetic cardiomyopathy
Degree: Ph.D.
Year: 2013
Subject: Ghrelin.
Ghrelin -- Physiological aspects.
Myocardium -- Diseases.
Hong Kong Polytechnic University -- Dissertations
Department: Dept. of Health Technology and Informatics
Pages: xxiv, 248 p. : ill. (some col.) ; 30 cm.
Language: English
InnoPac Record: http://library.polyu.edu.hk/record=b2653088
URI: http://theses.lib.polyu.edu.hk/handle/200/7287
Abstract: Cardiomyopathy is a well-known clinical problem in the heart that occurs during doxorubicin chemotherapy and in type 2 diabetic mellitus. Cardiac cell culture studies have showed that desacyl ghrelin, a preproghrelin gene-derived peptide, exerts favorable effects on cardiomyocytes such as inhibition of apoptosis. Nonetheless, the in vivo protective effects of desacyl ghrelin on cardiomyopathy have not been investigated. In this dissertation, we examined the protective effects of desacyl ghrelin on doxorubicin-induced cardiomyopathy and type 2 diabetic cardiomyopathy by using corresponding mouse experimental models. The number of diabetic cancer patients is rapidly increasing but the cardiac damaging effects of the anti-cancer drug doxorubicin on a diabetic heart have not been examined. As the signaling mechanisms of the doxorubicin-induced cardiomyopathy in a type 2 diabetic heart are mostly unknown, we further investigated the molecular signaling that is responsible for doxorubicin-induced cardiotoxicity in type 2 diabetic heart. The first part of this dissertation demonstrated that desacyl ghrelin improved the cardiac dysfunction induced by doxorubicin based on the functional results of ventricular fractional shortening and ejection fraction. Cardiac apoptosis and fibrosis induced by doxorubicin were prevented by desacyl ghrelin. Apoptotic DNA fragmentation, caspase-3 activity, apoptotic markers (Bcl-2, Bax and XIAP), fibrosis area and fibrotic regulatory factors (CTGF, BNP and TGF-β) were examined in cardiomyocytes. Desacyl ghrelin was found to exert protective effects on doxorubicin -induced cardiotoxicity via the attenuation of apoptosis and fibrosis through the activation of pro-survival ERK1/2/Akt signaling pathway. The second part of this dissertation showed that desacyl ghrelin alleviated cardiac dysfunction in type 2 diabetic cardiomyopathy indicated by the improvement of functional fractional shortening of ventricle. Collagen deposition, fibrotic regulatory factors, autophagic markers and AMPK/Akt/ERK1/2/GSK3α/β signaling pathway were examined. The results demonstrated that desacyl ghrelin reduced collagen deposition, up-regulated adiponectin expression, increased autophagic Beclin1 and Atg5-Atg12 conjugation, and enhanced phosphorylation of AMPK, Akt, ERK1/2 and GSK3α/β signaling in type 2 diabetic heart. The third part of this dissertation focused on examining the molecular mechanisms of the doxorubicin-induced cardiotoxicity in type 2 diabetic hearts by using the technique of microarray analysis. The results identified a panel of regulatory genes associated with cardiac remodeling, inflammatory response, oxidative stress, and DNA/RNA stability/repair in the doxorubicin-induced cardiac injury in diabetic heart. The results of this microarray experiment were confirmed by the analysis of transcript expression of selected genes by using real time PCR. Notably, the analysis suggested two important genes, namely S100A8 and S100A9, might play a unique role in the pathogenesis of the doxorubicin-induced cardiomyopathy specifically in diabetic heart.
In conclusion, the results of this dissertation evidently demonstrated the cardioprotective effects and the corresponding signaling mechanisms of desacyl ghrelin on the doxorubicin-induced cardiomyopathy and type 2 diabetic cardiomyopathy. These findings provide important pre-clinical information for future research to develop effective treatment or intervention in solving the clinical problem of the doxorubicin-induced cardiac toxicity in both non-diabetic and diabetic cancer patients.

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