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Published in:

01-12-2019

Acylated Ghrelin Protects the Hearts of Rats from Doxorubicin-Induced Fas/FasL Apoptosis by Stimulating SERCA2a Mediated by Activation of PKA and Akt

Authors: Ali A. Shati, M. Dallak

Published in: Cardiovascular Toxicology | Issue 6/2019

Abstract

This study investigated if the cardioprotective effect of acylated ghrelin (AG) against doxorubicin (DOX)-induced cardiac toxicity in rats involves inhibition of Fas/FasL-mediated cell death. It also investigated if such an effect is mediated by restoring Ca⁺² homeostasis from the aspect of stimulation of SERCA2a receptors. Adult male Wistar rats were divided into 4 groups (20 rats/each) as control, control + AG, DOX, and DOX + AG. AG was co-administered to all rats consecutively for 35 days. In addition, isolated cardiomyocytes were cultured and treated with AG in the presence or absence of DOX with or without pre-incubation with [d-Lys3]-GHRP-6 (a AG receptor antagonist), VIII (]an Akt inhibitor), or KT-5720 (a PKA inhibitor). AG increased LVSP, dp/dt_max, and dp/dt_min in both control and DOX-treated animals and improved cardiac ultrastructural changes in DOX-treated rats. It also inhibited ROS in control rats and lowered LVEDP, intracellular levels of ROS and Ca²⁺, and activity of calcineurin in LVs of DOX-treated rats. Concomitantly, it inhibited LV NFAT-4 nuclear translocation and downregulated their protein levels of Fas and FasL. Mechanistically, in control or DOX-treated hearts or cells, AG upregulated the levels of SERCA2a and increased the activities of PKA and Akt, leading to increase phosphorylation of phospholamban at Ser¹⁶ and Thr¹⁷. All these effects were abolished by d-Lys3-GHRP-6, VIII, or KT-5720 and were independent of food intake or GH/IGF-1. In conclusion, AG cardioprotection against DOX involves inhibition of extrinsic cell death and restoring normal Ca⁺² homeostasis.

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Title: Acylated Ghrelin Protects the Hearts of Rats from Doxorubicin-Induced Fas/FasL Apoptosis by Stimulating SERCA2a Mediated by Activation of PKA and Akt
Authors: Ali A. Shati
M. Dallak
Publication date: 01-12-2019
Publisher: Springer US
Published in: Cardiovascular Toxicology / Issue 6/2019
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-019-09527-8

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Acylated Ghrelin Protects the Hearts of Rats from Doxorubicin-Induced Fas/FasL Apoptosis by Stimulating SERCA2a Mediated by Activation of PKA and Akt

Abstract

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Abstract

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