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The hypertension drug Verapamil activates Nrf2 by promoting p62-dependent autophagic Keap1 degradation and prevents acetaminophen-induced cytotoxicity
Da Hyun Lee1,2, Jeong Su Park1,#, Yu Seol Lee1,#, Su Haeng Sung1, Yong-ho Lee3, Soo Han Bae1,*
1Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea,
2Brain Korea 21 PLUS Project for Medical Science, Yonsei University,
3Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) provides 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), an 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 of the protective role of verapamil against acetaminophen-induced cytotoxicity.
Abstract, Accepted Manuscript(in press) [Submitted on November 10, 2016, Accepted on December 13, 2016]
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