Bilirubin : A natural inhibitor of vascular smooth muscle cell proliferation

• Published in: Circulation (New York, N.Y.) Vol. 112; no. 7; pp. 1030 - 1039
• Main Authors: ÖLLINGER, Robert, BILBAN, Martin, OTTERBEIN, Leo E, USHEVA, Anny, YAMASHITA, Kenichiro, BACH, Fritz H, ERAT, Anna, FROIO, Alberto, MCDAID, James, TYAGI, Shivraj, CSIZMADIA, Eva, GRACA-SOUZA, Aurelio V, LILOIA, Angela, SCARES, Miguel P
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 16-08-2005
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Bilirubin - pharmacology; Biliverdine - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cell Differentiation - drug effects; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; Male; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Rats; Rats, Gunn; Rats, Inbred Lew; Rats, Wistar; Vertebrates: cardiovascular system; Cell proliferation; arteriosclerosis; muscle, smooth; Cell cycle; Cardiovascular disease; Smooth muscle; Bilirubin; signal transition
• DOI: 10.1161/CIRCULATIONAHA.104.528802
• EISSN: 1524-4539
• ISSN: 0009-7322

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