Bilirubin Is an Antioxidant of Possible Physiological Importance

Stocker, Roland; Yamamoto, Yorihiro; McDonagh, Antony F.; Glazer, Alexander N.; Ames, Bruce N.

doi:10.1126/science.3029864

Cited by 3,236 publications

(2,302 citation statements)

References 33 publications

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“…1,2 For example, the induction of ferritin by free iron has been shown to inhibit leukocyte migration, 27 proliferation of T cells 28 and to promote the development of DCs capable of inhibiting MLRs. 29 Bilirubin and biliverdin have been demonstrated to inhibit complement activation 30 and bilirubin has been described as a potent antioxidant, 31 as well as been shown to inhibit lymphocyte proliferation, IL-2 production and cytotoxicity. 32,33 Recently, CO has been shown to have antiinflammatory and protective roles in xenograft 34 and allograft rejection.…”

Section: Discussionmentioning

confidence: 99%

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

et al. 2004

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Elevated expression of heme oxygenase-1 (HO-1), an intracellular enzyme that degrades heme into carbon monoxide (CO), biliverdine and free iron, has anti-inflammatory and antiapoptotic effects in diverse models. Here, we analyzed the effects of specific overexpression of HO-1 following adenovirus-mediated (AdHO-1) gene transfer in an acute cardiac allograft rejection model. The intragraft (i.g.) injection of AdHO-1 into cardiac allografts, as well as intramuscular (i.m.) or intravenous (i.v.) administration, prolonged allograft survival with, respectively, 13.3, 62.5 and 80% of the grafts surviving long term (4100 days), whereas control grafts were rejected with acute kinetics. HO-1 overexpression was associated with inhibited allogeneic responses in MLRs using graft-infiltrating leukocytes and splenocytes, but not with lymph node cells. The inhibition of splenocyte proliferation was mediated by soluble factors and was dependent on the presence of APCs, since purified T cells proliferated normally. i.v. but not i.g. AdHO-1 administration decreased the number of graft-infiltrating leukocytes, cytokine mRNA accumulation and apoptosis in transplanted hearts, whereas i.v. and i.g. AdHO-1 did not modify normal immune responses against cognate antigens, indicating that there was no general immunosuppression. These results indicate that HO-1 overexpression prolongs the survival of vascularized allografts by promoting tolerogenic mechanisms acting on allogeneic cellular immune responses.

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Section: Discussionmentioning

confidence: 99%

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

et al. 2004

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“…We propose that oxidation of bilirubin produces molecules (BOXes) that cause or contribute to vasospasm. However, bilirubin itself has been shown to be an antioxidant (Dohi et al, 2003;Stocker et al, 1987Stocker et al, , 1990) and could therefore protect from vasospasm by decreasing oxidative stress. If bilirubin protects against oxidative stress and protects against vasospasm, and if bilirubin oxidation produces molecules that contribute to vasospasm, then whether vasospasm occurs may be of some balance between these two factors-BOX concentrations versus bilirubin concentrations.…”

Section: Chemistry and Oxidative Stress After Subarachnoid Hemorrhagementioning

confidence: 99%

BilirubinOxidation Products (BOXes) and Their Role in Cerebral Vasospasm after Subarachnoid Hemorrhage

Clark

Sharp

2006

J Cereb Blood Flow Metab

113

110

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Many factors have been postulated to cause delayed subarachnoid hemorrhage (SAH)-induced vasospasm, including hemoglobin, nitric oxide, endothelin, and free radicals. We propose that free radicals (because of the high levels that are produced in the blood clots surrounding blood vessels after SAH) act on bilirubin, biliverdin, and possibly heme to produce BOXes (Bilirubin OXidized Products). Bilirubin oxidation products act on vascular smooth muscle cells to produce chronic vasoconstriction and vasospasm combined with a vasculopathy because of smooth muscle cell injury. This review summarizes recent evidence that BOXes play a role in SAH-induced vasospasm. The data supporting a role for BOXes includes (1) identification of molecules in cerebrospinal fluid (CSF) of patients with vasospasm after SAH that have structures consistent with BOXes; (2) BOXes are vasoactive in vitro and mimic the biochemical actions of CSF of patients with vasospasm; (3) BOXes are vasoactive in vivo, constricting rat cerebral vessels; and (4) there is a correlation between clinical occurrence of vasospasm and BOXes concentration in our preliminary study of patients with SAH. Since oxidation of bilirubin, biliverdin, and perhaps heme is proposed to produce BOXes that contribute to vasospasm, either blocking bilirubin formation, inactivating bilirubin or BOXes, or removing all of the blood clot before vasospasm are potential treatment targets.

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“…8 Heme oxygenase (HO-1) is a potent antioxidant protein 9 that acts on heme, producing CO and biliverdin, which is further metabolized to bilirubin, a potent antioxidant itself. 10 HO-1 has been shown to be induced by Ang II 11 and HO-1 has been reported to reduce Ang IIinduced oxidative stress. 12 Upregulation of HO-1 protects against vascular diseases, including atherosclerosis via promoting re-endothelialization, inducing anti-inflammatory activities, inhibiting smooth-muscle-cell proliferation, regulating vascular tone and by increasing cellular antioxidant activities.…”

Section: Introductionmentioning

confidence: 99%

Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling

et al. 2011

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Angiotensin II (Ang II) is essential for endothelial progenitor cells (EPCs) function as Ang-II-induced oxidative stress causes senescence of EPCs and endothelial dysfunction and Ang II type 1 receptor blockers increase EPCs. Moreover, EPCs activity is dependent on nitric oxide (NO) and heme oxygenase (HO)-1 as these correlate with EPCs senescence and are reduced in hypertensives. Bartter's/Gitelman's syndrome patients (BS/GS), have increased Ang II yet normo/hypotension along with blunted Ang II signaling, reduced oxidative stress, increased NO and HO-1, thus presenting a unique system to explore EPC biology and its relationship with vascular clinical and biochemical correlates. Circulating EPCs, NO-dependent vasodilation (flow-mediated dilation (FMD)) and HO-1 gene expression were characterized in 10 BS/GS patients and in 10 normotensive subjects. EPCs defined by cell surface antigens CD34+kinase-insert domain receptor (KDR+), CD133+KDR+ and CD133+CD34+KDR+ cells were quantitiated via direct three-color flow-cytometry analysis, HO-1 gene expression by reverse transcription-PCR and FMD by B-mode echo scan of the right brachial artery. Correlation analysis was carried out regarding FMD and EPCs, FMD and HO-1 and EPCs and HO-1. In BS/GS, CD34+KDR+ cell numbers did not differ from controls while CD133+KDR+ and CD133+CD34+ KDR+ cell numbers were higher. HO-1 gene expression, as well as FMD, was higher in BS/GS compared with controls. Both CD133+KDR+ and CD133+CD34+KDR+ strongly correlated with both FMD and HO-1. FMD and HO-1 were also strongly correlated. These results document in a human system that EPC numbers and specific populations are related to important clinical and biochemical factors involved in cardiovascular (CV) status and reaffirm the utility of BS/GS patients as a useful system to investigate EPC's role(s) in the pathophysiology of cardiovascular remodeling in humans.

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Bilirubin Is an Antioxidant of Possible Physiological Importance

Cited by 3,236 publications

References 33 publications

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

BilirubinOxidation Products (BOXes) and Their Role in Cerebral Vasospasm after Subarachnoid Hemorrhage

Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling

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