sFRP1 has a biphasic effect on doxorubicin-induced cardiotoxicity in a cellular location-dependent manner in NRCMs and Rats
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Doxorubicin (Dox) is an effective anticancer drug, however, its clinical application is restricted by the life-threatening cardiotoxic effects. Secreted Frizzled-related protein 1 (sFRP1) has been reported to participate in both the cancer and cardiovascular diseases and was one of the differential expression genes in normal hearts compared with Dox-treated hearts. Thus, it is important to reveal the potential role of sFRP1 in Dox-induced cardiotoxicity. Here, we show that sFRP1 has a biphasic effect on Dox-induced cardiotoxicity in a location-dependent manner. The secretion of sFRP1 was significantly increased in Dox-treated neonatal rat cardiomyocytes (NRCMs) (1 µM) and SD rats (5 mg/kg/injection at day 1, 5, and 9, i.p.). Adding the anti-sFRP1 antibody (0.5 µg/ml) and inhibiting sFRP1 secretion by caffeine (5 mM) both relieved Dox-induced cardiotoxicity through activating Wnt/β-catenin signaling, whereas increasing the secretion of sFRP1 by heparin (100 µg/ml) had the opposite effect. The intracellular level of sFRP1 was significantly decreased after Dox treatment both in vitro and in vivo. Knockdown of sFRP1 by sgRNA aggravated Dox-induced cardiotoxicity, while moderate overexpression of sFRP1 by Ad-sFRP1 exhibited protective effect. Besides, poly(ADP-ribosyl) polymerase-1 (PARP1) was screened as an interacting partner of sFRP1 in NRCMs by mass spectrometry. Our results suggested that the intracellular sFRP1 protected NRCMs from Dox-induced cardiotoxicity by interacting with PARP1. Thus, our results provide a novel evidence that sFRP1 has a biphasic effect on Dox-induced cardiotoxicity. In addition, the oversecretion of sFRP1 might be used as a biomarker to indicate the occurrence of cardiotoxicity induced by Dox treatment.
KeywordssFRP1 Doxorubicin Cardiotoxicity Wnt/β-catenin PARP1
This research was supported by Grants from the 111 Project (No. B16047), National Natural Science Foundation of China (30670837, 81473205, 81673433, 81803521, 81872860), the Natural Science Foundation of Guangdong Province, China (No. 2016A030313211), Indigenous Innovative Research Team of Guangdong Province (2017BT01Y093), National Major Special Projects for the Creation and Manufacture of New Drugs (2018ZX09301031-001), Major Project of Platform Construction Education Department of Guangdong Province (No. 2014GKPT002), and Special Program for Applied Science and Technology of Guangdong Province (No. 2015B020232009 and 2014B020210003), National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004), Guangzhou Science and Technology Program Project (No. 201604020121), Medical Scientific Research Foundation of Guangdong Province (No. A2018078).
Compliance with ethical standards
Conflict of interest
All authors declare that there is no conflict of interest.
The animal experimental procedures were passed by the Research Ethics Committee of Sun Yat-sen University, and were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996).
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