Exp Mol Med.  2011 Jan;43(1):15-23. 10.3858/emm.2011.43.1.002.

Biliverdin reductase A in the prevention of cellular senescence against oxidative stress

• Kim SY
• Kang HT
• Choi HR
• Park SC

• KMID: 991619
• DOI: http://doi.org/10.3858/emm.2011.43.1.002

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 RNAitransfected 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 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.

Keyword

biliverdin reductase; cell aging; fibroblasts; heme oxygenase-1; reactive oxygen species

MeSH Terms

Age Factors
Blotting, Western
*Cell Aging
Cell Cycle
Cells, Cultured
Enzyme Induction
Fibroblasts/physiology
G1 Phase
Heme Oxygenase-1/metabolism
Humans
Hydrogen Peroxide/pharmacology
*Oxidative Stress
Oxidoreductases Acting on CH-CH Group Donors/*metabolism
Protein Kinase Inhibitors/metabolism
RNA, Small Interfering
Reactive Oxygen Species/metabolism
beta-Galactosidase/genetics/metabolism