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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

  • Ali A. ShatiEmail author
  • M. Dallak
Article
  • 7 Downloads

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/dtmax, and dp/dtmin 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.

Keywords

Ghrelin Doxorubicin Fas ligand Ca+2 NFAT 

Notes

Acknowledgments

The authors would like to thank the Animal facility staff at the King Khalid University (KKU), Abha, KSA for their help in taking care of animals, providing treatment, and arranging blood tissue collection. They would like also to thank the Physiology and Biochemistry technical staff at the College of Medicine at KKU for their contribution in the recording of the cardiovascular function of the experimental groups and helping in determination of some biochemical parameters. Furthermore, the authors would like to thank Dr. Reffat Eid, the Head of the Electron Microscope unit at the College of Medicine in the KKU for his significant contribution in the histology and electron microscopy studies. The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through the research group program under Grant Number (R.G.P.1/40/39).

Funding

This study was funded by the Deanship of Scientific Research at King Khalid University, Abha, Saudi Arabia (Grant Number R.G.P.1/40/39).

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biology, College of ScienceKing Khalid UniversityAbhaSaudi Arabia
  2. 2.Department of Physiology, College of MedicineKing Khalid UniversityAbhaSaudi Arabia

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