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The hypertension drug, verapamil, activates Nrf2 by promoting p62-dependent autophagic Keap1 degradation and prevents acetaminophen-induced cytotoxicity

Authors
 Da Hyun Lee  ;  Jeong Su Park  ;  Yu Seol Lee  ;  Su Haeng Sung  ;  Yong-ho Lee  ;  Soo Han Bae 
Citation
 BMB Reports, Vol.50(2) : 91-96, 2017 
Journal Title
 BMB Reports 
ISSN
 1976-6696 
Issue Date
2017
MeSH
Acetaminophen/toxicity* ; Animals ; Antihypertensive Agents/pharmacology* ; Autophagy/drug effects ; Autophagy/genetics ; Cells, Cultured ; Cytoprotection*/drug effects ; Cytoprotection*/genetics ; HEK293 Cells ; Humans ; Kelch-Like ECH-Associated Protein 1/genetics ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Mice ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress/drug effects ; Oxidative Stress/genetics ; Proteolysis/drug effects ; Reactive Oxygen Species/metabolism ; Verapamil/pharmacology*
Keywords
APAP ; Keap1 ; Nrf2 ; Oxidative stress ; Verapamil
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) provides a cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist, verapamil, is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity, through degradation of Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 repressor. Furthermore, verapamilinduced Keap1 degradation is prominently mediated by a p62-dependent autophagic pathway. Correspondingly, verapamil protects cells from acetaminophen-induced oxidative damage through Nrf2 activation. These results demonstrated the underlying mechanisms for the protective role of verapamil against acetaminophen-induced cytotoxicity. [BMB Reports 2017; 50(2): 91-96].
Files in This Item:
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DOI
10.5483/BMBRep.2017.50.2.188
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
배수한(Bae, Soo Han) ORCID logo https://orcid.org/0000-0002-8007-2906
이용호(Lee, Yong Ho) ORCID logo https://orcid.org/0000-0002-6219-4942
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/154656
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