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


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.
Ollinger
Robert
R
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. robert.oellinger@uibk.ac.at
Bilban
Martin
M
Erat
Anna
A
Froio
Alberto
A
McDaid
James
J
Tyagi
Shivraj
S
Csizmadia
Eva
E
Graça-Souza
Aurelio V
AV
Liloia
Angela
A
Soares
Miguel P
MP
Otterbein
Leo E
LE
Usheva
Anny
A
Yamashita
Kenichiro
K
Bach
Fritz H
FH
D000818:Animals; D001663:Bilirubin / Q000494:pharmacology*; D001664:Biliverdine / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D011911:Rats, Gunn; D011917:Rats, Inbred Lew; D017208:Rats, Wistar
D001664:Biliverdine; D001663:Bilirubin