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http://dx.doi.org/10.5483/BMBRep.2017.50.2.188

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)
Publication Information
BMB Reports / v.50, no.2, 2017 , pp. 91-96 More about this Journal
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
APAP; Keap1; Nrf2; Oxidative stress; Verapamil;
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