Published Online
on August 8, 2005

A more recent version of this article appeared on August 16, 2005

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Submitted on December 11, 2004
Revised on April 25, 2005
Accepted on April 27, 2005

Bilirubin. A Natural Inhibitor of Vascular Smooth Muscle Cell Proliferation

Robert Öllinger MD^*, Martin Bilban PhD, Anna Erat , Alberto Froio MD, James McDaid MD, Shivraj Tyagi PhD, Eva Csizmadia , Aurelio V. Graça-Souza PhD, Angela Liloia MD, Miguel P. Soares PhD, Leo E. Otterbein PhD, Anny Usheva PhD, Kenichiro Yamashita MD, PhD, and Fritz H. Bach MD

From the Departments of Surgery (R.Ö., M.B., A.E., A.F., J.M., S.T., E.C., A.V.G.-S., A.L., L.E.O., K.Y., F.H.B.) and Medicine (A.E., A.U.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; Department of Surgery, Innsbruck Medical University, Innsbruck, Austria (R.Ö.); and Gulbenkian Institute for Science, Oeiras, Portugal (M.P.S.).

^* To whom correspondence should be addressed. E-mail: fritz_bach{at}hms.harvard.edu,.

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.

Key words: arteriosclerosis • bilirubin • cell cycle • muscle, smooth • signal transition

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