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.
journal_name
Cardiovasc Toxicoljournal_title
Cardiovascular toxicologyauthors
Shati AA,Dallak Mdoi
10.1007/s12012-019-09527-8subject
Has Abstractpub_date
2019-12-01 00:00:00pages
529-547issue
6eissn
1530-7905issn
1559-0259pii
10.1007/s12012-019-09527-8journal_volume
19pub_type
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