Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation.

Abstract

BACKGROUND:

Bilirubin, a natural product of heme catabolism by heme oxygenases, was considered a toxic waste product until 1987, when its antioxidant potential was recognized. On the basis of observations that oxidative stress is a potent trigger in vascular proliferative responses, that heme oxygenase-1 is antiatherogenic, and that several studies now show that individuals with high-normal or supranormal levels of plasma bilirubin have a lesser incidence of atherosclerosis-related diseases, we hypothesized that bilirubin would have salutary effects on preventing intimal hyperplasia after balloon injury.

METHODS AND RESULTS:

We found less balloon injury-induced neointima formation in hyperbilirubinemic Gunn rats and in wild-type rats treated with biliverdin, the precursor of bilirubin, than in controls. In vitro, bilirubin and biliverdin inhibited serum-driven smooth muscle cell cycle progression at the G1 phase via inhibition of the mitogen-activated protein kinase signal transduction pathways and inhibition of phosphorylation of the retinoblastoma tumor suppressor protein.

CONCLUSIONS:

Bilirubin and biliverdin might be potential therapeutics in vascular proliferative disorders.

• Authors: Robert Ollinger, Martin Bilban, Anna Erat, Alberto Froio, James McDaid, Shivraj Tyagi, Eva Csizmadia, Aurelio V Graça-Souza, Angela Liloia, Miguel P Soares, Leo E Otterbein, Anny Usheva, Kenichiro Yamashita, Fritz H Bach
• Journal: Circulation (Circulation) Vol. 112 Issue 7 Pg. 1030-9 (Aug 16 2005) ISSN: 1524-4539 [Electronic] United States
• PMID: 16087796 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biliverdine
• Bilirubin

Topics

• Animals
• Bilirubin (pharmacology)
• Biliverdine (pharmacology)
• Cell Differentiation (drug effects)
• Male
• Muscle, Smooth, Vascular (cytology, drug effects)
• Rats
• Rats, Gunn
• Rats, Inbred Lew
• Rats, Wistar