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Biliverdin Reductase A Protects Lens Epithelial Cells against Oxidative Damage and Cellular Senescence in Age-Related Cataract

ABSTRACT: Age-related cataract (ARC) is the common cause of blindness globally. Reactive oxygen species (ROS), one of the greatest contributors to aging process, leads to oxidative damage and senescence of lens epithelial cells (LECs), which are involved in the pathogenesis of ARC. Biliverdin reductase A (BVRA) has ROS-scavenging ability by converting biliverdin (BV) into bilirubin (BR). However, little is known about the protective effect of BVRA against ARC. In the present study, we measured the expression level of BVRA and BR generation in human samples. Then, the antioxidative property of BVRA was compared between the young and senescent LECs upon stress condition. In addition, we evaluated the effect of BVRA on attenuating H2O2-induced premature senescence in LECs. The results showed that the mRNA expression level of BVRA and BR concentration were decreased in both LECs and lens cortex of age-related nuclear cataract. Using the RNA interference technique, we found that BVRA defends LECs against oxidative stress via (i) restoring mitochondrial dysfunction in a BR-dependent manner, (ii) inducing heme oxygenase-1 (HO-1) expression directly, and (iii) promoting phosphorylation of ERK1/2 and nuclear delivery of nuclear factor erythroid 2-related factor 2 (Nrf2). Intriguingly, the antioxidative effect of BVRA was diminished along with the reduced BR concentration and repressed nuclear translocation of BVRA and Nrf2 in senescent LECs, which would be resulted from the decreased BVRA activity and impaired nucleocytoplasmic trafficking. Eventually, we confirmed that BVRA accelerates the G1 phase transition and prevents against H2O2-induced premature senescence in LECs. In summary, BVRA protects LECs against oxidative stress and cellular senescence in ARC by converting BV into BR, inducing HO-1 expression, and activating the ERK/Nrf2 pathway. This trial is registered with ChiCTR2000036059.

SUBMITTER: Huang Y

PROVIDER: S-EPMC9325611 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Increased cell senescence contributes to the pathogenesis of aging and aging-related disease. Senescence of human fibroblasts in vitro may be delayed by culture in low glucose concentration. There is also accumulating evidence of senescence delay by exposure to dietary bioactive compounds that activate transcription factor Nrf2. The mechanism of cell senescence delay and connection between these responses is unknown. We describe herein that the cruciferous vegetable-derived metabolite, sulforaphane (SFN), activates Nrf2 and delays senescence of human MRC-5 and BJ fibroblasts in vitro. Cell senescence is associated with a progressive and marked increased rate of glucose metabolism through glycolysis. This increases mitochondrial dysfunction and overwhelms defences against reactive metabolites, leading to increasing proteomic and genomic oxidative damage. Increased glucose entry into glycolysis in fibroblast senescence is mainly mediated by increased hexokinase-2. SFN delayed senescence by decreasing glucose metabolism on the approach to senescence, exhibiting a caloric restriction mimetic-like activity and thereby decreased oxidative damage to cell protein and DNA. This was associated with increased expression of thioredoxin-interacting protein, curbing entry of glucose into cells; decreased hexokinase-2, curbing entry of glucose into cellular metabolism; decreased 6-phosphofructo-2-kinase, downregulating formation of allosteric enhancer of glycolysis fructose-2,6-bisphosphate; and increased glucose-6-phosphate dehydrogenase, downregulating carbohydrate response element- (ChRE-) mediated transcriptional enhancement of glycolysis by Mondo/Mlx. SFN also enhanced clearance of proteins cross-linked by transglutaminase which otherwise increased in senescence. This suggests that screening of compounds to counter senescence-associated glycolytic overload may be an effective strategy to identify compounds with antisenescence activity and health beneficial effects of SFN in longevity may involve delay of senescence through glucose and glycolytic restriction response.

Project description:Background:Proliferative vitreoretinopathy (PVR) is a severe blinding complication of retinal detachment surgery. Increasing evidence demonstrate that PVR is associated with oxidative stress. Scutellarin is a natural flavone compound that has been reported to have anti-oxidative activity. However, the effect of scutellarin on PVR remains unknown. In the current study, we assessed the effect of scutellarin on hydrogen peroxide (H2O2)-induced oxidative injury in human retinal pigment epithelium cells (ARPE-19). Methods:ARPE-19 cells were pretreated with different concentrations of scutellarin for 2 h, and then challenged with H2O2 (1 mM) for 24 h. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) and glutathione (GSH) activity were measured to assess the level of oxidative stress. Flow cytometry was performed to detect the apoptosis rate of ARPE-19 cells. Expression levels of bcl-2, bax, cleaved-caspase-3, p-JAK2, JAK2, p-STAT3, and STAT3 were measured using western blot. Results:Our results revealed that scutellarin improved the cell viability of H2O2-induced ARPE-19 cells. Scutellarin alleviated the H2O2-induced oxidative stress in ARPE-19 cells, which was illustrated by reduced levels of ROS and MDA, accompanied by increased SOD activity and GSH level. The increased apoptosis rate of ARPE-19 cells caused by H2O2 induction was significantly decreased after scutellarin treatment. H2O2 treatment resulted in significant increase in bax expression and decrease in bcl-2 expression, while the changes in the expressions of bax and bcl-2 were reversed by scutellarin treatment. In addition, scutellarin promoted the activation of JAK2/STAT3 signaling pathway in H2O2-induced ARPE-19 cells. Suppression of JAK2/STAT3 signaling pathway abolished the protective effects of scutellarin on H2O2-induced ARPE-19 cells. Conclusion:These findings suggested that scutellarin was capable for alleviating H2O2-induced oxidative damage in ARPE-19 cells, which might be ascribed to the activation of JAK2/STAT3 signaling pathway.

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Biliverdin Reductase A Protects Lens Epithelial Cells against Oxidative Damage and Cellular Senescence in Age-Related Cataract

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