Fibroblast growth factor-2-mediated protection of cardiomyocytes from the toxic effects of doxorubicin requires the mTOR/Nrf-2/HO-1 pathway
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Navid Koleini1,2, Barbara E. Nickel1, Jie Wang2, Zeinab Roveimiab1, Robert R. Fandrich1,3, Lorrie A. Kirshenbaum1,2, Peter A. Cattini2 and Elissavet Kardami1,2,3
1Institute of Cardiovascular Sciences, Albrechtsen Research Centre, Winnipeg, Manitoba, Canada
2Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
3Department of Human Anatomy and Cell Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
Elissavet Kardami, email: [email protected]
Keywords: fibroblast growth factor 2 isoforms, doxorubicin cardiotoxicity, heme oxygenase 1 cardioprotection, Nrf-2 activation, mTOR signaling
Received: June 22, 2017 Accepted: August 04, 2017 Published: August 24, 2017
Background: Cardiotoxic side effects impose limits to the use of anti-tumour chemotherapeutic drugs such as doxorubicin (Dox). There is a need for cardioprotective strategies to prevent the multiple deleterious effects of Dox. Here, we examined the ability of administered fibroblast growth factor-2 (FGF-2), a cardioprotective protein that is synthesized as high and low molecular weight (Hi-, Lo-FGF-2) isoforms, to prevent Dox-induced: oxidative stress; cell death; lysosome dysregulation; and inactivation of potent endogenous protective pathways, such as the anti-oxidant/detoxification nuclear factor erythroid-2-related factor (Nrf-2), heme oxygenase-1 (HO-1) axis.
Methods and Results: Brief pre-incubation of neonatal rat cardiomyocyte cultures with either Hi- or Lo-FGF-2 reduced the Dox-induced: oxidative stress; apoptotic/necrotic cell death; lysosomal dysregulation; decrease in active mammalian target of Rapamycin (mTOR). FGF-2 isoforms prevented the Dox-induced downregulation of Nrf-2, and promoted robust increases in the Nrf-2-downstream targets including the cardioprotective protein HO-1, and p62/SQSTM1, a multifunctional scaffold protein involved in autophagy. Chloroquine, an autophagic flux inhibitor, caused a further increase in p62/SQSTM1, indicating intact autophagic flux in the FGF-2-treated groups. A selective inhibitor for HO-1, Tin-Protoporphyrin, prevented the FGF-2 protection against cell death. The mTOR inhibitor Rapamycin prevented FGF-2 protection, and blocked the FGF-2 effects on Nrf-2, HO-1 and p62/SQSTM1.
Conclusions: In an acute setting, Hi- or Lo-FGF-2 protect cardiomyocytes against multiple Dox-induced deleterious effects, by a mechanism dependent on preservation of mTOR activity, Nrf-2 levels, and the upregulation of HO-1. Preservation/activation of endogenous anti-oxidant/detoxification defences by FGF-2 is a desirable property in the setting of Dox-cardiotoxicity.
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