Biliverdin reductase A in the prevention of cellular senescence against oxidative stress
Biliverdin reductase A in the prevention of cellular senescence against oxidative stress
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DOI：
10.3858/emm.2011.43.1.002
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发表时间：
2011-01-31
影响因子：
12.8
通讯作者：
Park, Sang Chul
中科院分区：
文献类型：
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作者：
Kim, Sung Young;Kang, Hyun Tae;Park, Sang Chul
胆绿素还原酶A（BLVRA），一种将胆绿素转化为胆红素的酶，最近已成为细胞氧化还原循环的关键调节剂。然而，BLVRA在衰老过程中的作用仍不清楚。为了研究BLVRA在衰老过程中的作用，我们比较了年轻和衰老的人二倍体成纤维细胞（HDF）对活性氧（ROS）诱导剂过氧化氢（H2 O2）的应激反应。H_2O_2在年轻的HDFs中显著诱导BLVRA活性，但在衰老的HDFs中不诱导。此外，耗尽BLVRA减少了H2 O2依赖的诱导血红素加氧酶-1（HO-1）在年轻的HDFs，但不是在衰老的细胞，这表明一个老化依赖性的差异调制的氧化应激反应。当BLVRA表达降低的慢病毒RNAi转染稳定的原代HDF显示CDK抑制剂家族成员p16、p53和p21上调，随后细胞周期停滞在G（0）-G（1）期并高表达衰老相关β-半乳糖苷酶时，证实了BLVRA在细胞衰老调控中的作用。综上所述，这些数据支持BLVRA通过调节细胞氧化状态而显著调节衰老过程的观点。
Biliverdin reductase A (BLVRA), an enzyme that converts biliverdin to bilirubin, has recently emerged as a key regulator of the cellular redox cycle. However, the role of BLVRA in the aging process remains unclear. To study the role of BLVRA in the aging process, we compared the stress responses of young and senescent human diploid fibroblasts (HDFs) to the reactive oxygen species (ROS) inducer, hydrogen peroxide (H2O2). H2O2 markedly induced BLVRA activity in young HDFs, but not in senescent HDFs. Additionally, depletion of BLVRA reduced the H2O2-dependent induction of heme oxygenase-1 (HO-1) in young HDFs, but not in senescent cells, suggesting an aging-dependent differential modulation of responses to oxidative stress. The role of BLVRA in the regulation of cellular senescence was confirmed when lentiviral RNAi-transfectal stable primary HDFs with reduced BLVRA expression showed upregulation of the CDK inhibitor family members p16, p53, and p21, followed by cell cycle arrest in G(0)-G(1) phase with high expression of senescence-associated beta-galactosidase. Taken together, these data support the notion that BLVRA contributes significantly to modulation of the aging process by adjusting the cellular oxidative status.