Absence of the biliverdin reductase-a gene is associated with increased endogenous oxidative stress

Chen, Wei-Yu; Maghzal, Ghassan J.; Ayer, Anita; Suarna, Cacang; Dunn, Louise; Stocker, Roland

doi:10.1016/j.freeradbiomed.2017.11.020

Cited by 59 publications

(78 citation statements)

References 54 publications

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“…Also, inhibition of HO-1 activity in stress induced endothelial cells has demonstrated increased sensitivity to ROS mediated damage, with restored effects of cell viability attributed to the addition of bilirubin 44 . A gene deletion of biliverdin reductase has further been associated with increased endogenous oxidative stress 45 , suggestive of a direct role for bilirubin in conferring protection by HO-1, albeit that carbon monoxide, another by-product of the catabolic heme pathway can also confer neuroprotection 46 .…”

Section: Discussionmentioning

confidence: 99%

Evidence supporting oxidative stress in a moderately affected area of the brain in Alzheimer’s disease

Youssef

Chami

Lim

et al. 2018

Sci Rep

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The pathogenesis of Alzheimer’s disease (AD) remains to be elucidated. Oxidative damage and excessive beta-amyloid oligomers are components of disease progression but it is unclear how these factors are temporally related. At post mortem, the superior temporal gyrus (STG) of AD cases contains plaques, but displays few tangles and only moderate neuronal loss. The STG at post mortem may represent a brain region that is in the early stages of AD or alternately a region resistant to AD pathogenesis. We evaluated expression profiles and activity of endogenous anti-oxidants, oxidative damage and caspase activity in the STG of apolipoprotein ε4-matched human AD cases and controls. Total superoxide dismutase (SOD) activity was increased, whereas total glutathione peroxidase (GPX), catalase (CAT) and peroxiredoxin (Prx) activities, were decreased in the AD-STG, suggesting that hydrogen peroxide accumulates in this brain region. Transcripts of the transcription factor NFE2L2 and inducible HMOX1, were also increased in the AD-STG, and this corresponded to increased Nuclear factor erythroid 2-related factor (NRF-2) and total heme-oxygenase (HO) activity. The protein oxidation marker 4-hydroxynonenal (4-HNE), remained unchanged in the AD-STG. Similarly, caspase activity was unaltered, suggesting that subtle redox imbalances in early to moderate stages of AD do not impact STG viability.

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Section: Discussionmentioning

confidence: 99%

Evidence supporting oxidative stress in a moderately affected area of the brain in Alzheimer’s disease

Youssef

Chami

Lim

et al. 2018

Sci Rep

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“…The possible related biological mechanisms of the role of bilirubin on lung function in COPD patients have been reported [ 14 – 17 ]. When heme is degraded to biliverdin by heme oxygenase, the production of bilirubin begins [ 14 ]. Biliverdin is subsequently reduced to bilirubin by biliverdin reductase [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…When heme is degraded to biliverdin by heme oxygenase, the production of bilirubin begins [ 14 ]. Biliverdin is subsequently reduced to bilirubin by biliverdin reductase [ 14 ]. Heme oxygenase-1 (HO-1), the inducible isoform of heme oxygenase expressed in type 2 pneumocytes and alveolar macrophages in the lung, has been reported to be up-regulated by oxidative stress and hypoxia [ 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

Association of serum bilirubin level with lung function decline: a Korean community-based cohort study

Leem

Kim

et al. 2018

Respir Res

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BackgroundBilirubin has been reported to be associated with respiratory diseases due to its antioxidant action. We aimed to evaluate the relationship between serum bilirubin concentration and annual lung function decline in the Korean general population.MethodsThe study included 7986 subjects aged 40–69 years from the Ansung-Ansan cohort database I (2001–2002)–III (2005–2006). We analyzed the relationships between serum bilirubin level and forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, and mean forced expiratory flow between 25 and 75% of FVC (FEF25–75%) at baseline, as well as the annual average changes in these lung parameters.ResultsThe FEV1, FVC, and FEF25–75% were significantly associated with serum bilirubin levels after adjustment for age, sex, body mass index (BMI), and smoking status (all P < 0.001). When stratified according to smoking status, these relationships were significant in never-smokers. Additionally, serum bilirubin level was negatively associated with the annual decline in FEV1 and FVC, and positively associated with the annual decline in FEV1/FVC after adjustment for age, sex, BMI, baseline lung function, and smoking status (all P < 0.001).ConclusionsWe found significant associations of serum bilirubin levels with FEV1, FVC, and FEF25–75% in the general population, especially in never-smokers. Moreover, serum bilirubin levels were related with the annual decline in FEV1, FVC, and FEV1/FVC ratio.

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“…Although both isozymes catalyze the reduction of biliverdin, BVR-A selectively reduces biliverdin IXα to bilirubin IXα, one of the strongest endogenous antioxidants [3,4]. For that reason, BVR-A has been studied for a long time as an antioxidant enzyme capable of counteracting oxidative stress-induced alterations [1,2,5].…”

Section: Introductionmentioning

confidence: 99%

BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain—Implications for Neurodegeneration

et al. 2020

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Biliverdin reductase-A (BVR-A) impairment is associated with increased accumulation of oxidatively-damaged proteins along with the impairment of autophagy in the brain during neurodegenerative disorders. Reduced autophagy inhibits the clearance of misfolded proteins, which then form neurotoxic aggregates promoting neuronal death. The aim of our study was to clarify the role for BVR-A in the regulation of the mTOR/autophagy axis by evaluating age-associated changes (2, 6 and 11 months) in cerebral cortex samples collected from BVR-A knock-out (BVR-A−/−) and wild-type (WT) mice. Our results show that BVR-A deficiency leads to the accumulation of oxidatively-damaged proteins along with mTOR hyper-activation in the cortex. This process starts in juvenile mice and persists with aging. mTOR hyper-activation is associated with the impairment of autophagy as highlighted by reduced levels of Beclin-1, LC3β, LC3II/I ratio, Atg5–Atg12 complex and Atg7 in the cortex of BVR-A−/− mice. Furthermore, we have identified the dysregulation of AMP-activated protein kinase (AMPK) as a critical event driving mTOR hyper-activation in the absence of BVR-A. Overall, our results suggest that BVR-A is a new player in the regulation of autophagy, which may be targeted to arrive at novel therapeutics for diseases involving impaired autophagy.

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Absence of the biliverdin reductase-a gene is associated with increased endogenous oxidative stress

Cited by 59 publications

References 54 publications

Evidence supporting oxidative stress in a moderately affected area of the brain in Alzheimer’s disease

Evidence supporting oxidative stress in a moderately affected area of the brain in Alzheimer’s disease

Association of serum bilirubin level with lung function decline: a Korean community-based cohort study

BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain—Implications for Neurodegeneration

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