on August 8, 2005
Published online before print August 8, 2005, doi: 10.1161/CIRCULATIONAHA.104.528802
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Submitted on December 11, 2004
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.
Revised on April 25, 2005
Accepted on April 27, 2005
Bilirubin. A Natural Inhibitor of Vascular Smooth Muscle Cell Proliferation
Robert Öllinger MD*,
Key words: arteriosclerosis • bilirubin • cell cycle • muscle, smooth • signal transition
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Circulation 2005 112: 935.
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