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KMID : 0624620170500020091
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BMB Reports
2017 Volume.50 No. 2 p.91 ~ p.96
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The hypertension drug, verapamil, activates Nrf2 by promoting p62-dependent autophagic Keap1 degradation and prevents acetaminophen-induced cytotoxicity
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Lee Da-Hyun
Park Jeong-Su
Lee Yu-Seol
Sung Su-Haeng
Lee Yong-Ho
Bae Soo-Han
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Abstract
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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.
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KEYWORD
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APAP, Keap1, Nrf2, Oxidative stress, Verapamil
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