Published online before print August 8, 2005, doi: 10.1161/CIRCULATIONAHA.104.528802
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(Circulation. 2005;112:1030-1039.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Bilirubin
A Natural Inhibitor of Vascular Smooth Muscle Cell Proliferation
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.).
Correspondence to Robert Öllinger, MD, Anny Usheva, PhD, or Fritz H. Bach, MD, 99 Brookline Ave, Research North, RN 361, Boston, MA 02215. E-mail fritz_bach{at}hms.harvard.edu, ausheva@bidmc.harvard.edu, or robert.oellinger@uibk.ac.at
Received December 11, 2004; revision received April 25, 2005; accepted April 27, 2005.
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.
CLINICAL PERSPECTIVE
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