Bilirubin and biliverdin treatment of atherosclerotic diseases.
We have recently shown that the natural bile pigment bilirubin has antiproliferative effects on vascular smooth muscle cells (VSMCs). Bilirubin is the end product of heme catabolism mediated by heme oxygenases and has for decades been considered a toxic waste product of our bodies. However, 14 separate studies and a meta-analysis have documented an inverse correlation between atherosclerosis and the levels of bilirubin in normal individuals. Having high normal or supranormal levels of bilirubin is associated with less atherosclerotic-type disease as compared with that in individuals with low normal levels of bilirubin. This combined with experimental data showing anti-atherosclerotic properties of the enzyme heme oxygenase-1 encouraged us to hypothesize that bilirubin and its precursor biliverdin, would act to ameliorate components of atherosclerosis, in a manner similar to what has been shown with HO-1. Both did so in an animal model of restenosis in which vascular smooth muscle cell proliferation leads to intimal proliferation and causes narrowing of the vessels. We also analyzed the antiproliferative effects of the bile pigments in an in vitro system where bilirubin/biliverdin caused p53 dependent cell cycle arrest by hypophosphorylation of the retinoblastoma tumor suppressor protein in growth factor stimulated VSMCs.
Ollinger
Robert
R
Department of Surgery, Innsbruck Medical University, Innsbruck, Austria. robert.oellinger@i-med.ac.at
Yamashita
Kenichiro
K
Bilban
Martin
M
Erat
Anna
A
Kogler
Pamela
P
Thomas
Michael
M
Csizmadia
Eva
E
Usheva
Anny
A
Margreiter
Raimund
R
Bach
Fritz H
FH
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D001663:Bilirubin / Q000627:therapeutic use*; D001664:Biliverdine / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D008297:Male; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew
D016895:Culture Media, Serum-Free; D001664:Biliverdine; D001663:Bilirubin