Acylated ghrelin prevents doxorubicin-induced cardiac intrinsic cell death and fibrosis in rats by restoring IL-6/JAK2/STAT3 signaling pathway and inhibition of STAT1

  • Ali A. ShatiEmail author
  • Attalla Farag El-kott
Original Article


This study investigated if JAK/STAT signaling pathway mediates doxorubicin (DOX)-induced cell death and fibrosis in left ventricles (LVs) of rats and examined if acylated ghrelin affords protection by modulating this pathway. Male rats (120 ± 5 g) were divided into 6 groups (10 rats each) as follows: control; control + AG (10 ng/kg, s.c.); DOX (an accumulative dose 15 mg/kg, i.p.); DOX + AG, DOX + AG + AG490, a JAK2 inhibitor (5 mg/kg, i.p.); and DOX + AG + [D-Lys3]-GHRP-6; an AG receptor antagonist (3.75 mg/kg, i.p.). All treatments were carried out for 35 days. In rats’ LVs, DOX significantly impaired the systolic and diastolic functions, enhanced levels of ROS and MDA, reduced levels of GSH and Bcl-2, and increased mRNA and protein levels of collagen I/III and TGF-β and cleaved caspase-3. In addition, although DOX did not affect JAK1 or JAK2 activity, it significantly increased protein levels of IL-6, decreased STAT3 and p-STAT3 (Tyr701&Ser727), and increased STAT1 and p-STAT1 (Tyr701&Ser727) levels, with a concomitant decrease in ERK1/2 activity and an increase in P38 activity. However, without affecting IL-6 and JAK1/2, AG reversed all of the observed alterations with a significant increase in the levels and activities of JAK2. Similar effects of AG were also seen in control rats. Interestingly, all the beneficial effects afforded by AG were abolished by AG490 and AG + [D-Lys3]-GHRP-6. In conclusion, DOX-induced cardiac toxicity involves stimulation of IL-6, P38, and STAT1 signaling levels whereas the protective effect afforded by AG involves the activation of ERK1/2 and JAK2/STAT3 and inhibition of STAT1.


Ghrelin Doxorubicin JAK/STAT IL-6 Rats 



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 the animals, treatment, and blood tissue collection. They would like also to thank Mr. Mahmoud Alkhateeb from the College of Medicine at King Saud University of Health Sciences and the technical staff members of the Physiology and Biochemistry in the College of Medicine at KKU for their contribution in the recording of the cardiovascular function of the experimental groups and helping in the determination of some biochemical parameters. Furthermore, the authors would like to thank Dr. Reffat Eid, from the Pathology Department at the College of Medicine in KKU for his significant contribution in the histology, immunohistochemistry, 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).

Author contributions

AS conceived and designed the research. AS and AFE conducted the experiments. AS analyzed and graphed the data. AS and AFEK wrote and revised the manuscript. AS and AFE read and approved the final version of the manuscript.


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

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards for the use and care of laboratory animals at King Khalid University, Abha, KSA.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Biology Department, College of ScienceKing Khalid UniversityAbhaSaudi Arabia
  2. 2.Zoology Department, College of ScienceDamanhour UniversityDamanhourEgypt

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