Koleini Navid, Nickel Barbara E, Wang Jie, Roveimiab Zeinab, Fandrich Robert R, Kirshenbaum Lorrie A, Cattini Peter A, Kardami Elissavet
Institute of Cardiovascular Sciences, Albrechtsen Research Centre, Winnipeg, Manitoba, Canada.
Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada.
Oncotarget. 2017 Aug 24;8(50):87415-87430. doi: 10.18632/oncotarget.20558. eCollection 2017 Oct 20.
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.
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.
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.
心脏毒性副作用限制了多柔比星（Dox）等抗肿瘤化疗药物的使用。需要采取心脏保护策略来预防Dox的多种有害影响。在此，我们研究了给予成纤维细胞生长因子-2（FGF-2）（一种以高分子量和低分子量（Hi-FGF-2、Lo-FGF-2）异构体形式合成的心脏保护蛋白）预防Dox诱导的氧化应激、细胞死亡、溶酶体失调以及有效内源性保护途径失活（如抗氧化/解毒核因子红细胞2相关因子（Nrf-2）、血红素加氧酶-1（HO-1）轴）的能力。
用Hi-FGF-2或Lo-FGF-2对新生大鼠心肌细胞培养物进行短暂预孵育，可减少Dox诱导的氧化应激、凋亡/坏死性细胞死亡、溶酶体失调以及活性哺乳动物雷帕霉素靶蛋白（mTOR）的降低。FGF-2异构体可预防Dox诱导的Nrf-2下调，并促进Nrf-2下游靶点的显著增加，包括心脏保护蛋白HO-1以及参与自噬的多功能支架蛋白p62/SQSTM1。自噬通量抑制剂氯喹导致p62/SQSTM1进一步增加，表明FGF-2处理组的自噬通量完整。HO-1的选择性抑制剂锡原卟啉可预防FGF-2对细胞死亡的保护作用。mTOR抑制剂雷帕霉素可预防FGF-2的保护作用，并阻断FGF-2对Nrf-2、HO-1和p62/SQSTM1的影响。
在急性情况下，Hi-FGF-2或Lo-FGF-2通过依赖于维持mTOR活性、Nrf-2水平以及上调HO-1的机制保护心肌细胞免受多种Dox诱导的有害影响。FGF-2对内源性抗氧化/解毒防御的保存/激活在Dox心脏毒性的情况下是一种理想的特性。
