Bilirubin

Abstract

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 atherosclerosisrelated 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 G 1 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. (Circulation.

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

“…It has been previously reported that bilirubin administration was vasoprotective in a rat model of vascular balloon injury [50], similar to that seen with HO-1 overexpression, suggesting that one component of the cytoprotective effects of HO-1 is likely mediated by bilirubin and/or biliverdin. For example, prior studies have shown that administration of bilirubin inhibited JNK phosphorylation, c-Jun phosphorylation, and endothelial cell apoptosis [51].…”

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

“…29 Neointimal proliferation seen two weeks after angioplasty (balloon injury) in wild type rats was virtually absent in the hyperbilirubinemic rats. 30 In concert with those findings, a one-hour local pretreatment of the carotid artery of a naïve, wild type rat with biliverdin was able very significantly to reduce neointima formation following balloon injury (Fig. 1A).…”

“…When these cells were treated with bilirubin or its precursor biliverdin, 3 H-thymidine uptake was significantly reduced upon FCS stimulation in a dose dependent manner. 30 No significant increase in apoptotic cells was observed after bilirubin/biliverdin treatment at concentrations up to 200mM, but a highly significant portion of the cells were held in the G 0 /G 1 phase when compared to the control (Fig. 1B).…”

“…30 We further tested VSMCs cultured from mice genetically deficient for either p21 or p53 to ascertain the importance of these molecules in the bilirubin/biliverdin effects. In p21 -/-VSMCs, bilirubin/ biliverdin were as effective in inhibiting 3 H-thymidine incorporation as in the wild type counterparts, however, the lack of p53 abrogated the antiproliferative effect of bilirubin/biliverdin, suggesting that the antiproliferative properties of bilirubin/biliverdin require p53 but are independent of p21 ( Fig.…”

Biliverdin inhibits activation of NF‐κB: Reversal of inhibition by human biliverdin reductase

“…[9][10][11][12][13][14][15][16][17] Oxidative stress has been linked to the etiology of a wide spectrum of pathophysiological conditions, including cancer, neurological disorders and inflammatory diseases. [18][19][20][21][22] The contribution of hBVR to antioxidant protection offered by induction of the stress-inducible ho-1 was demonstrated by the observation that inhibition of hBVR, by siRNA treatment potentiates ROS-mediated damage to cells and promotes apoptosis. 23 BVR is known as a biliverdin-converting enzyme; however, recent findings have uncovered additional functions of the human reductase that relate to its kinase activity and reflect its structural features.…”