Tat-Biliverdin Reductase A Exerts a Protective Role in Oxidative Stress-Induced Hippocampal Neuronal Cell Damage by Regulating the Apoptosis and MAPK Signaling

Abstract

Reactive oxygen species (ROS) is major risk factor in neuronal diseases including ischemia. Although biliverdin reductase A (BLVRA) plays a pivotal role in cell survival via its antioxidant function, its role in hippocampal neuronal (HT-22) cells and animal ischemic injury is not clearly understood yet. In this study, the effects of transducible fusion protein Tat-BLVRA on H2O2-induced HT-22 cell death and in an animal ischemia model were investigated. Transduced Tat-BLVRA markedly inhibited cell death, DNA fragmentation, and generation of ROS. Transduced Tat-BLVRA inhibited the apoptosis and mitogen activated protein kinase (MAPK) signaling pathway and it passed through the blood-brain barrier (BBB) and significantly prevented hippocampal cell death in an ischemic model. These results suggest that Tat-BLVRA provides a possibility as a therapeutic molecule for ischemia.

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

“…Neuroblastoma cells lacking BVR-A are unable to activate the Akt/GSK3β axis, thus appearing more susceptible to H 2 O 2 -induced oxidative damage [21]. Furthermore, induction of BVR-A was reported to prevent hippocampal cell death by inhibiting DNA fragmentation and generation of reactive oxygen species in an ischemic model [22].…”

Protective effect of GK2 fused BLVRA protein against oxidative stress‐induced dopaminergic neuronal cell damage

“…Also, GK2-BLVRA protein increased Caspase-9 and -3 expressions, whereas expression of cleaved Caspase-9 and -3 protein decreased under the same conditions. We have reported that Tat-BLVRA protein increased Caspase-8, -9 and -3 expression levels in H 2 O 2 -exposed HT-22 cells [30] and other studies have shown that biliverdin reductase enhanced cell survival by inhibiting death receptor-5, cytochrome c or caspase-3 activity [52,53]. Our results are consistent with the study by Song et al [54] in which they have shown that biliverdin reductase prevented apoptosis of pulmonary arterial smooth muscle cell (PASMC) by inhibiting mitochondrial dysfunction and increasing Bcl-2, Caspase-9 and -3 expressions in the cells.…”

“…Thus PTDs have been applied as effective vehicles to deliver therapeutic molecules like protein, DNA, RNA, liposome and nanoparticles into cells because they have the ability to transduce into cells [21,22]. Among them, Tat-PTD derived from the human immunodeficiency virus is widely used to deliver the therapeutic protein into cells [23][24][25], and many groups have shown that Tat-fusion protein is transduced into a variety of cells, which were markedly protected against oxidative stress-induced cell death [26][27][28][29][30][31][32][33].…”

Transcriptome sequencing reveals genes involved in cadmium-triggered oxidative stress in the chicken heart

“…Gene ontology term analysis ( Figure 4 A) showed that these genes were enriched in oxidative stress–related terms, including tissue development ( Monteiro et al., 2017 ), negative regulation of cell differentiation ( Chen et al., 2018 ) keratinocyte proliferation ( Smirnov et al., 2016 ), and positive regulation of cell cycle ( Baeeri et al., 2019 ). And the KEGG analysis determined that these differentially expressed genes were mostly enriched in pathways such as the transforming growth factor-beta signaling pathway, focal adhesion, the Wnt signaling pathway, regulation of the actin cytoskeleton, and the MAPK signaling pathway, which were implicated in oxidative stress ( Farah et al., 2011 ; Lu et al., 2011 ; Lou et al., 2018 ; Zhang et al., 2018b ; Kim et al., 2020 ) ( Figure 4 B).

Figure 4 GO and KEGG enrichment analysis of Cd-induced differentially expressed genes.

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