Abstract
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- transfected 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 G0-G1 phase with high expression of senescence-associated β-galactosidase. Taken together, these data support the notion that BLVRA contributes significantly to modulation of the aging process by adjusting the cellular oxidative status.
Highlights
Reactive oxygen species (ROS) are involved in the pathogenesis of various human diseases and in the aging process
In order to test the relationship of Biliverdin reductase A (BLVRA) with cellular senescence, we first compared BLVRA activity in young and senescent human diploid fibroblast cells (HDF) cells in response to H2O2 treatment
BLVRA was initially known as an enzyme that converts biliverdin to bilirubin
Summary
Reactive oxygen species (ROS) are involved in the pathogenesis of various human diseases and in the aging process. Recent studies have shown that BLVRA has ROS-scavenging abilities through its production of bilirubin, a potent physiological antioxidant (Baranano et al, 2002; Florczyk et al, 2008; Wu et al, 2008; Sedlak et al, 2009). Tudor et al (2008) have shown that BLVRA is involved in the regulation of HO-1 expression. This efficient antioxidative system consisting of cyclic cellular redox control and induction of HO-1 by BLVRA may fortify the capacity of bilirubin as one of the most effective physiological defense molecules against cellular oxidative stress
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