title: Deletion of thioredoxin interacting protein (TXNIP) augments hyperoxia-induced vaso-obliteration in a mouse model of oxygen induced-retinopathy.
abstract: We have recently shown that thioredoxin interacting protein (TXNIP) is required for VEGF-mediated VEGFR2 receptor activation and angiogenic signal. Retinas from TXNIP knockout mice (TKO) exhibited higher cellular antioxidant defense compared to wild type (WT). This study aimed to examine the impact of TXNIP deletion on hyperoxia-induced vaso-obliteration in ischemic retinopathy. TKO and WT pups were subjected to oxygen-induced retinopathy model. Retinal central capillary dropout was measured at p12. Retinal redox and nitrative state were assessed by reduced-glutathione (GSH), thioredoxin reductase activity and nitrotyrosine formation. Western blot and QT-PCR were used to assess VEGF, VEGFR-2, Akt, iNOS and eNOS, thioredoxin expression, ASK-1 activation and downstream cleaved caspase-3 and PARP in retinal lysates. Retinas from TKO mice exposed to hyperoxia showed significant increases (1.5-fold) in vaso-obliteration as indicated by central capillary drop out area compared to WT. Retinas from TKO showed minimal nitrotyrosine levels (10% of WT) with no change in eNOS or iNOS mRNA expression. There was no change in levels of VEGF or activation of VEGFR2 and its downstream Akt in retinas from TKO and WT. In comparison to WT, retinas from TKO showed significantly higher level of GSH and thioredoxin reductase activity in normoxia but comparable levels under hyperoxia. Exposure of TKO to hyperoxia significantly decreased the anti-apoptotic thioredoxin protein (∼ 50%) level compared with WT. This effect was associated with a significant increase in activation of the apoptotic ASK-1, PARP and caspase-3 pathway. Our results showed that despite comparable VEGF level and signal in TKO, exposure to hyperoxia significantly decreased Trx expression compared to WT. This effect resulted in liberation and activation of the apoptotic ASK-1 signal. These findings suggest that TXNIP is required for endothelial cell survival and homeostasis especially under stress conditions including hyperoxia.
authors.affiliation: Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia, United States of America; Department of Physiology, Georgia Regents University, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Abdelsaid
authors.affiliation: Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia, United States of America; Culver Vision Discovery Institute, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Suraporn
authors.initials: S
authors.lastname: Matragoon
authors.affiliation: Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia, United States of America; Department of Physiology, Georgia Regents University, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.affiliation: Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia, United States of America; Culver Vision Discovery Institute, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Azza B
authors.initials: AB
authors.lastname: El-Remessy
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D018496:Hyperoxia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; C445672:Txnip protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D013879:Thioredoxins; D010100:Oxygen