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

被引：38

作者：

Lee, Da Hyun ^{[1
,2
]}

Park, Jeong Su ^{[1
]}

Lee, Yu Seol ^{[1
]}

Sung, Su Haeng ^{[1
]}

Lee, Yong-ho ^{[3
]}

Bae, Soo Han ^{[1
]}

机构：

[1] Yonsei Univ, Coll Med, Yonsei Biomed Res Inst, Severance Biomed Sci Inst, Seoul 03722, South Korea

[2] Yonsei Univ, Brain Korea PLUS Project Med Sci 21, Seoul 03722, South Korea

[3] Yonsei Univ, Div Endocrinol & Metab, Dept Internal Med, Coll Med, Seoul 03722, South Korea

来源：

BMB REPORTS | 2017年 / 50卷 / 02期

基金：

新加坡国家研究基金会;

关键词：

APAP; Keap1; Nrf2; Oxidative stress; Verapamil; CALCIUM-CHANNEL BLOCKERS; NONALCOHOLIC STEATOHEPATITIS; INDUCED HEPATOTOXICITY; TRANSCRIPTION FACTOR; SELECTIVE AUTOPHAGY; OXIDATIVE STRESS; PATHWAY; MECHANISM; CELLS; MICE;

D O I：

10.5483/BMBRep.2017.50.2.188

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：91 / 96

页数：6

共 35 条

[1]

Sestrins Activate Nrf2 by Promoting p62-Dependent Autophagic Degradation of Keap1 and Prevent Oxidative Liver Damage [J].