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Thioredoxin-interacting protein mediates nuclear-to-plasma membrane communication: role in vascular endothelial growth factor 2 signaling.

ABSTRACT: Thioredoxin-interacting protein (TXNIP) and poly-ADP-ribose polymerase 1 (PARP1) are both regulated by changes in cellular reduction-oxidation (redox) state and localize to the nucleus basally in human umbilical vein endothelial cells (HUVEC). Previously we showed a novel mechanism for PARP1 inhibition-mediated HUVEC survival through activation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling in response to stress-induced apoptosis. In addition, we showed TXNIP translocation to the plasma membrane (PM) and activation of VEGFR2 in response to physiological stimuli. Because TXNIP is an ?-arrestin that regulates VEGFR2 signaling, we hypothesized that PARP1 regulates TXNIP localization and function that might affect HUVEC stress-induced apoptosis.HUVEC treated with 10 ?mol/L PARP1 inhibitor (PJ34) were protected from TNF (10 ng/mL) or H(2)O(2) (300 ?mol/L) mediated cell death. HUVEC transfected with TXNIP siRNA lost the protective effect of PARP1 inhibition, suggesting a protective role for TXNIP. Using immunofluorescence, cell fractionation analysis, and plasma membrane sheet assay, TXNIP was shown to translocate to the plasma membrane after PARP1 inhibition. TXNIP translocation was associated with activation of VEGFR2 signaling. Functionally, TXNIP-PARP1 interaction was decreased on PJ34 treatment, suggesting PARP1 as a novel regulator of TXNIP localization and function.These findings demonstrate a novel regulatory mechanism of TXNIP by PARP1 to mediate activation of plasma membrane signaling and cell survival.

SUBMITTER: Spindel ON

PROVIDER: S-EPMC3876410 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Thioredoxin-interacting protein mediates nuclear-to-plasma membrane communication: role in vascular endothelial growth factor 2 signaling.

Spindel Oded N ON Yan Chen C Berk Bradford C BC

Arteriosclerosis, thrombosis, and vascular biology 20120216 5

<h4>Objective</h4>Thioredoxin-interacting protein (TXNIP) and poly-ADP-ribose polymerase 1 (PARP1) are both regulated by changes in cellular reduction-oxidation (redox) state and localize to the nucleus basally in human umbilical vein endothelial cells (HUVEC). Previously we showed a novel mechanism for PARP1 inhibition-mediated HUVEC survival through activation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling in response to stress-induced apoptosis. In addition, we showed TXN ...[more]

PMID: 22345166

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Project description:PURPOSE:To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN:Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS:Participants with available plasma samples (N = 436). METHODS:Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES:Changes in the natural log (ln) of plasma VEGF levels. RESULTS:Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS:These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

Dataset Information

Thioredoxin-interacting protein mediates nuclear-to-plasma membrane communication: role in vascular endothelial growth factor 2 signaling.

Publications

Thioredoxin-interacting protein mediates nuclear-to-plasma membrane communication: role in vascular endothelial growth factor 2 signaling.

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