Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts

Yamashita, Kazuo; McDaid, James; Öllinger, Robert; Tsui, Ting Y.; Berberat, Pascal O.; Usheva, Anny; Csizmadia, Eva; Smith, R. Neal; Soares, Miguel P.; Bach, Fritz H.

doi:10.1096/fj.03-0839fje

Cited by 169 publications

(158 citation statements)

References 36 publications

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“…We assume that it is the effect of increased bilirubin/biliverdin, as in Gunn rats or rats carotid arteries treated with biliverdin, on VSMC cell cycle progression that suppresses neointimal proliferation after balloon injury, as reagents inhibiting cell cycle progression in VSMCs do have antiatherosclerotic properties. 1,2 We cannot rule out that at least in part the anti-inflammatory 32,33 and/or immunosuppressive 34,35 properties that have been attributed to bilirubin/biliverdin may contribute to our observations.…”

Section: Discussionmentioning

confidence: 83%

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Öllinger¹,

Yamashita²,

Bilban³

et al. 2007

Cell Cycle

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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.

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Section: Discussionmentioning

confidence: 83%

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Öllinger¹,

Yamashita²,

Bilban³

et al. 2007

Cell Cycle

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“…It has been reported that IL-2 can play an antiinflammatory role during early phases of CIA induction, but is proinflammatory in established disease (32). Previous studies have demonstrated that carbon monoxide inhibits T cell proliferation and IL-2 secretion (33), and biliverdin has been shown to inhibit IL-2 transcription and T cell proliferation in a murine model of heart transplantation (15). Our results in established CIA support the concept that HO-1 activity could exert immunosuppressive effects.…”

Section: Discussionmentioning

confidence: 99%

“…We obtained [5,6,8,11,12,14,15(N)-3 H]-prostaglandin E 2 (PGE 2 ) from Amersham Biosciences (Barcelona, Spain). Cyclooxygenase 2 (COX-2)-specific polyclonal antibody was purchased from Cayman Chemical (Ann Arbor, MI).…”

Section: Methodsmentioning

confidence: 99%

“…In inflammatory and immune conditions, high levels of mediators with the potential to induce HO-1 are produced, and the expression of this protein could be part of an adaptive mechanism for limiting cytotoxicity via several means, including radical scavenging or inhibition of cell proliferation and apoptosis (9,10). The beneficial effects of HO-1 overexpression have been shown in a number of conditions, such as endotoxemia (11), lung hyperoxia (12), atherogenesis (13), myocardial injury after ischemiareperfusion (14), and cardiac allograft survival (15). HO-1 induction has also been shown to down-regulate the inflammatory response in animal models of acute inflammation.…”

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confidence: 99%

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Influence of heme oxygenase 1 modulation on the progression of murine collagen‐induced arthritis

Devesa¹,

Ferrándiz²,

Terencio³

et al. 2005

Arthritis & Rheumatism

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Objective. Heme oxygenase 1 (HO-1) can be induced by inflammatory mediators as an adaptive response. The objective of the present study was to determine the consequences of HO-1 modulation in the murine collagen-induced arthritis (CIA) model.Methods. DBA/1J mice were treated with an inhibitor of HO-1, tin protoporphyrin IX (SnPP), or with an inducer of HO-1, cobalt protoporphyrin IX (CoPP), from day 22 to day 29 after CIA induction. The clinical evolution of disease was monitored visually. At the end of the experiment, joints were examined for histopathologic changes. Cytokine levels in paws were measured by enzyme-linked immunosorbent assay. Levels of HO-1, cyclooxygenase 2 (COX-2), and prostaglandin E 2 (PGE 2 ) were determined. Effects of treatments on the early phase of disease and after prophylactic administration were also assessed.Results. CoPP strongly induced HO-1, resulting in the inhibition of cartilage erosion accompanied by extensive fibrosis in the joint. Levels of tumor necrosis factor ␣ (TNF␣), interleukin-2 (IL-2), and IL-10 were inhibited by CoPP, whereas levels of vascular endothelial growth factor were increased. Treatment with SnPP significantly reduced the severity of CIA, with inhibition of joint inflammation and cartilage destruction. The levels of PGE 2 , IL-1␤, and TNF␣ were also significantly reduced by SnPP treatment, which did not modify COX-2 protein expression. SnPP was more effective than CoPP in preventing the development of CIA (prophylactic administration).Conclusion. HO-1 is induced during CIA. Although overexpression of this protein causes some beneficial effects, strategies aimed at HO-1 overexpression cannot slow the progression of the chronic inflammatory disease, whereas treatment with SnPP, which inhibits HO-1, exerts prophylactic and therapeutic effects.

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“…It has been demonstrated that treatment with biliverdin enhances tolerance of cardiac allografts, and that this tolerance is mediated by inhibition of the transcription factors NFAT and NF-jB. 61 As a clinically relevant example, it has been reported that low levels of bilirubin correlate with an increased incidence of inflammatory coronary artery disease. 62 Conversely, a genetic predisposition of persons with moderately increased levels of bilirubin, as is observed in Gilbert syndrome, significantly reduces the incidence.…”

Section: Discussionmentioning

confidence: 99%

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

Gibbs

Maines

2007

Intl Journal of Cancer

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hBVR functions in the cell as a reductase and as a kinase. In the first capacity, it reduces biliverdin, the product of HO activity, to the effective intracellular antioxidant, bilirubin; as a dual-specificity kinase (S/T/Y) it activates the MAPK and IGF/IRK receptor signal transduction pathways. NF-jB and the MAPK pathway are activated by ROS, which results in the activation of stress-inducible genes, including ho-1. Presently, we report on the negative effect of biliverdin on NF-jB activation and the converse effect of hBVR. Biliverdin, in a concentration-and time-dependent manner, inhibited transcriptional activity of NF-jB in HEK293A cells. Nuclear extracts from biliverdin-treated cells show reduced DNA binding of NF-jB in an electromobility shift assay, whereas extracts from cells treated with TNF-a showed enhanced binding. Coimmunoprecipitation data show hBVR binds to the 65 kDa subunit of NF-jB, and that this is dependent on activation by TNF-a. Overexpression of hBVR enhanced both the basal and TNF-amediated activation of NF-jB and also that of the NF-jB-activated iNOS gene. Also, overexpression of hBVR arrested the cell cycle in the G 1 /G 0 phase and reduced the number of cells in S phase. Similar results were observed with MCF-7 cells. Because of the Janus nature of NF-jB activity in the cell and the inhibitory action of biliverdin, the present findings provide a foundation for therapeutic intervention in inflammatory diseases and cancer that may be attained by preventing reduction of biliverdin. On the other hand, by increasing BVR levels beneficial functions of NF-jB might be augmented. ' 2007 Wiley-Liss, Inc.

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Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts

Cited by 169 publications

References 36 publications

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Influence of heme oxygenase 1 modulation on the progression of murine collagen‐induced arthritis

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

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