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Atorvastatin protects cardiomyocyte from doxorubicin toxicity by modulating survivin expression through FOXO1 inhibition

Authors
 Jaewon Oh  ;  Beom Seob Lee  ;  Gibbeum Lim  ;  Heejung Lim  ;  Chan Joo Lee  ;  Sungha Park  ;  Sang-Hak Lee  ;  Ji Hyung Chung  ;  Seok-Min Kang 
Citation
 JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol.138 : 244-255, 2020-02 
Journal Title
 JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 
ISSN
 0022-2828 
Issue Date
2020-02
Keywords
Apoptosis ; Cardiotoxicity ; Statin
Abstract
BACKGROUND: Survivin has an anti-apoptotic effect against anthracycline-induced cardiotoxicity. Clinically, statin use is associated with a lower risk for heart failure in breast cancer patients with anthracycline chemotherapy. So, the purpose of our study was to investigate whether survivin mediates the protective effect of statin against anthracycline-induced cardiotoxicity. METHODS: Mice were treated once a week with 5 mg/kg doxorubicin for 4 weeks with or without atorvastatin 20 mg/kg every day then heart tissues were analyzed. Molecular and cellular biology analyses were performed with H9c2 cell lysates. RESULTS: Doxorubicin suppressed survivin expression via activation of FOXO1 in H9c2 cardiomyocytes. Whereas, atorvastatin inhibited FOXO1 by increasing phosphorylation and inhibiting nuclear localization. Doxorubicin induced FOXO1 binding to STAT3 and prevented STAT3 from interacting with Sp1. However, atorvastatin inhibited these interactions and stabilized STAT3/Sp1 transcription complex. Chromatin immunoprecipitation analysis demonstrated that doxorubicin decreased STAT3/Sp1 complex binding to survivin promoter, whereas atorvastatin stabilized this binding. In mouse model, atorvastatin rescued doxorubicin-induced reduction of survivin expression and of heart function measured by cardiac magnetic resonance imaging. CONCLUSIONS: Our study suggested a new pathophysiologic mechanism that survivin mediated protective effect of atorvastatin against doxorubicin-induced cardiotoxicity via FOXO1/STAT3/Sp1 transcriptional network.
Full Text
https://www.sciencedirect.com/science/article/pii/S0022282819303979
DOI
10.1016/j.yjmcc.2019.12.007
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Min(강석민) ORCID logo https://orcid.org/0000-0001-9856-9227
Park, Sung Ha(박성하) ORCID logo https://orcid.org/0000-0001-5362-478X
Oh, Jae Won(오재원) ORCID logo https://orcid.org/0000-0002-4585-1488
Lee, Sang Hak(이상학) ORCID logo https://orcid.org/0000-0002-4535-3745
Lee, Chan Joo(이찬주) ORCID logo https://orcid.org/0000-0002-8756-409X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/174906
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