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Cell Tissue Res. 2018 Dec;374(3):607-617. doi: 10.1007/s00441-018-2905-z. Epub 2018 Aug 29.

Non-mitogenic FGF2 protects cardiomyocytes from acute doxorubicin-induced toxicity independently of the protein kinase CK2/heme oxygenase-1 pathway.

Author information

1
Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre., 351 Tache Ave, Winnipeg, Manitoba, R2H2A6, Canada.
2
Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada.
3
Department of Human Anatomy and Cell Sciences, University of Manitoba, Winnipeg, Canada.
4
Interventional Cardiology, Section of Cardiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.
5
Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre., 351 Tache Ave, Winnipeg, Manitoba, R2H2A6, Canada. ekardami@sbrc.ca.
6
Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada. ekardami@sbrc.ca.
7
Department of Human Anatomy and Cell Sciences, University of Manitoba, Winnipeg, Canada. ekardami@sbrc.ca.

Abstract

Doxorubicin (Dox)-induced cardiotoxicity, a limiting factor in the use of Dox to treat cancer, can be mitigated by the mitogenic factor FGF2 in vitro, via a heme oxygenase 1 (HO-1)-dependent pathway. HO-1 upregulation was reported to require protein kinase CK2 activity. We show that a mutant non-mitogenic FGF2 (S117A-FGF2), which does not activate CK2, is cardioprotective against acute cardiac ischemic injury. We now investigate the potential of S117A-FGF2 to protect cardiomyocytes against acute Dox injury and decrease Dox-induced upregulation of oxidized phospholipids. The roles of CK2 and HO-1 in cardiomyocyte protection are also addressed.Rat neonatal cardiomyocyte cultures were used as an established in vitro model of acute Dox toxicity. Pretreatment with S117A-FGF2 protected against Dox-induced: oxidative stress; upregulation of fragmented and non-fragmented oxidized phosphatidylcholine species, measured by LC/MS/MS; and cardiomyocyte injury and cell death measured by LDH release and a live-dead assay. CK2 inhibitors (TBB and Ellagic acid), did not affect protection by S117A-FGF2 but prevented protection by mitogenic FGF2. Furthermore, protection by S117A-FGF2, unlike that of FGF2, was not prevented by HO-1 inhibitors and S117A-FGF2 did not upregulate HO-1. Protection by S117A-FGF2 required the activity of FGF receptor 1 and ERK.We conclude that mitogenic and non-mitogenic FGF2 protect from acute Dox toxicity by common (FGFR1) and distinct, CK2/HO-1- dependent or CK2/HO-1-independent (respectively), pathways. Non-mitogenic FGF2 merits further consideration as a preventative treatment against Dox cardiotoxicity.

KEYWORDS:

Acute doxorubicin cardiotoxicity; CK2-HO-1 signaling; Non-mitogenic FGF2; Oxidized phospholipids; Rat cardiomyocytes

PMID:
30159756
PMCID:
PMC6267702
DOI:
10.1007/s00441-018-2905-z
[Indexed for MEDLINE]
Free PMC Article

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