The Interplay Between Peroxiredoxin-2 and Nuclear Factor-Erythroid 2 Is Important in Limiting Oxidative Mediated Dysfunction in β-Thalassemic Erythropoiesis

Mattè, Alessandro; Falco, Luigia De; Iolascon, Achille; Mohandas, Narla; An, Xiuli; Siciliano, Angela; Lebœuf, Christophe; Janin, Anne; Bruno, Mariasole; Choi, Soo Young; Kim, Dae Won; Franceschi, Lucia De

doi:10.1089/ars.2014.6237

Cited by 46 publications

(58 citation statements)

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“…Flow cytometric analysis of erythroid precursors from bone marrow was carried out using the CD44-TER-119 using the FACSCanto IITM flow cytometer (Becton Dickinson). Population II, III and IV were sorted from bone marrow, as previously reported43. Morphological analysis of sorted erythroblasts was performed on cytospin preparations stained with May Grunwald-Giemsa.…”

Section: Methodsmentioning

confidence: 99%

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Porreca

D’Angelo

Franceschi

et al. 2016

Sci Rep

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In vitro Omics analysis (i.e. transcriptome) is suggested to predict in vivo toxicity and adverse effects in humans, although the causal link between high-throughput data and effects in vivo is not easily established. Indeed, the chemical-organism interaction can involve processes, such as adaptation, not established in cell cultures. Starting from this consideration we investigate the transcriptomic response of immortalized thyrocytes to ethylenthiourea and chlorpyrifos. In vitro data revealed specific and common genes/mechanisms of toxicity, controlling the proliferation/survival of the thyrocytes and unrelated hematopoietic cell lineages. These results were phenotypically confirmed in vivo by the reduction of circulating T4 hormone and the development of pancytopenia after long exposure. Our data imply that in vitro toxicogenomics is a powerful tool in predicting adverse effects in vivo, experimentally confirming the vision described as Tox21c (Toxicity Testing in the 21st century) although not fully recapitulating the biocomplexity of a living animal.

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Section: Methodsmentioning

confidence: 99%

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Porreca

D’Angelo

Franceschi

et al. 2016

Sci Rep

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“…We analyzed 10 erythroid cultures from the peripheral blood of different normal subjects and 8 erythroid cultures from Immunoblot analysis of human erythroid precursors Details on immunoblot analysis 39 are reported in the supplemental Materials and methods. 22,39,40 Immunofluorescence assay for LAMP1 and MitoTrack and LisoTrack analysis on erythroid precursors and reticulocyte-enriched fraction Details are provided in supplemental Materials and methods. 41 …”

Section: Cell Culture and Functional Analysismentioning

confidence: 99%

A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

Lupo

Tibaldi

Mattè

et al. 2016

Blood

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Key Points• In chorea-acanthocytosis, spiculated red cells are characterized by heightened Lyn kinase activity and dysregulated autophagy.• Regulation of protein turnover by autophagy plays a key role in erythropoiesis and red cell integrity.Chorea-acanthocytosis is one of the hereditary neurodegenerative disorders known as the neuroacanthocytoses. Chorea-acanthocytosis is characterized by circulating acanthocytes deficient in chorein, a protein of unknown function. We report here for the first time that chorea-acanthocytosis red cells are characterized by impaired autophagy, with cytoplasmic accumulation of active Lyn and of autophagy-related proteins Ulk1 and Atg7. In chorea-acanthocytosis erythrocytes, active Lyn is sequestered by HSP90-70 to form high-molecular-weight complexes that stabilize and protect Lyn from its proteasomal degradation, contributing to toxic Lyn accumulation. An interplay between accumulation of active Lyn and autophagy was found in chorea-acanthocytosis based on Lyn coimmunoprecipitation with Ulk1 and Atg7 and on the presence of Ulk1 in Lyncontaining high-molecular-weight complexes. In addition, chorein associated with Atg7 in healthy but not in chorea-acanthocytosis erythrocytes. Electron microscopy detected multivesicular bodies and membrane remnants only in circulating chorea-acanthocytosis red cells. In addition, reticulocyte-enriched chorea-acanthocytosis red cell fractions exhibited delayed clearance of mitochondria and lysosomes, further supporting the impairment of authophagic flux. Because autophagy is also important in erythropoiesis, we studied in vitro CD341 -derived erythroid precursors. In chorea-acanthocytosis, we found (1) dyserythropoiesis; (2) increased active Lyn; (3) accumulation of a marker of autophagic flux and autolysososme degradation; (4) accumlation of Lamp1, a lysosmal membrane protein, and LAMP1-positive aggregates; and (5) reduced clearance of lysosomes and mitochondria. Our results uncover in choreaacanthocytosis erythroid cells an association between accumulation of active Lyn and impaired autophagy, suggesting a link between chorein and autophagic vesicle trafficking in erythroid maturation. (Blood. 2016;128(25):2976-2987

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“…C57BL/6 Hx -/-mice and Hbb th3/+ mice as a model of β-thalassemia were described previously [20,[25][26][27][28][29]. All mice were housed in our animal facility, with a 12-h dark/light cycle and access to standard laboratory chow and tap water ad libitum.…”

Section: Mice and Treatmentsmentioning

confidence: 99%

“…No evidences of collagen deposition or leukocyte infiltration in Hx -/-heart were observed, despite a slight transcriptional up-regulation of pro-inflammatory Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) (see Figure 5 in [37]). To dissect the cardiotoxic effect of free heme, we evaluated systolic function in Hbb th3/+ mice used as model of non-transfusion dependent β-thalassemia intermedia [29,42]. Interestingly, a similar systolic dysfunction was observed in β-thalassemic mice ( Figure 3D-F and Table 2) that are hallmarked by a high rate of intravascular hemolysis as evidenced by Hx depletion in serum, HO-1 induction at mRNA and protein level in the heart and altered cardiac expression of iron and anti-oxidant genes (see Figure 6 in [37]).…”

Section: Hemopexin Prevents Heme Overload-induced Heart Dysfunctionmentioning

confidence: 99%

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Ingoglia

Sag

Rex

et al. 2017

Free Radical Biology and Medicine

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Heart failure is a leading cause of morbidity and mortality in patients affected by different disorders associated to intravascular hemolysis. The leading factor is the presence of pathologic amount of pro-oxidant free heme in the bloodstream, due to the exhaustion of the natural heme scavenger Hemopexin (Hx). Here, we evaluated whether free heme directly affects cardiac function, and tested the therapeutic potential of replenishing serum Hx for increasing serum heme buffering capacity.The effect of heme on cardiac function was assessed in vitro, on primary cardiomyocytes and H9c2 myoblast cell line, and in vivo, in Hx -/-mice and in genetic and acquired mouse models of intravascular hemolysis. Purified Hx or anti-oxidants N-Acetyl-L-cysteine and α-tocopherol were used to counteract heme cardiotoxicity.In mice, Hx loss/depletion resulted in heme accumulation and enhanced reactive oxygen species (ROS) production in the heart, which ultimately led to severe systolic dysfunction. Similarly, high ROS reduced systolic Ca 2+ transient amplitudes and fractional shortening in primary cardiomyocytes exposed to free heme. In keeping with these Ca 2+ handling alterations, oxidation and CaMKIIdependent phosphorylation of Ryanodine Receptor 2 were higher in Hx -/-hearts than in controls.Administration of anti-oxidants prevented systolic failure both in vitro and in vivo. Intriguingly, Hx rescued contraction defects of heme-treated cardiomyocytes and preserved cardiac function in hemolytic mice.We show that heme-mediated oxidative stress perturbs cardiac Ca 2+ homeostasis and promotes contractile dysfunction. Scavenging heme, Hx counteracts cardiac heme toxicity and preserves left ventricular function. Our data generate the rationale to consider the therapeutic use of Hx to limit the cardiotoxicity of free heme in hemolytic disorders.

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The Interplay Between Peroxiredoxin-2 and Nuclear Factor-Erythroid 2 Is Important in Limiting Oxidative Mediated Dysfunction in β-Thalassemic Erythropoiesis

Abstract: Our data shed new light on adaptive mechanisms against oxidative damage through the interplay of Prx2 and Nrf2 during stress erythropoiesis and suggest new therapeutic options to decrease ineffective erythropoiesis by modulation of endogenous antioxidant systems.

Cited by 46 publications

References 47 publications

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

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