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

  • Lee, Da Hyun (Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Park, Jeong Su (Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Lee, Yu Seol (Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Sung, Su Haeng (Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Lee, Yong-ho (Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Bae, Soo Han (Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine)
  • Received : 2016.11.10
  • Accepted : 2016.12.13
  • Published : 2017.02.28

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, verapamil-induced 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.

Keywords

References

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