Differential regulation of redox proteins and chaperones in HbEβ‐thalassemia erythrocyte proteome

Bhattacharya, Dipankar; Saha, Sutapa; Basu, Sumanta; Chakravarty, Sudipa; Chakravarty, Amit; Banerjee, Debashis; Chakrabarti, Abhijit

doi:10.1002/prca.200900073

Cited by 41 publications

(66 citation statements)

References 35 publications

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“…We observed that antioxidant proteins, chaperone proteins, proteins involving in iron metabolism, hemoglobin subunit d, cathepsin S (an inflammatory marker), and erythroid proteins were consistently increased in quantity in HbE/ b-thalassemic patients across all 3 pooled samples (Table 2), and this was also observed in 6 individual samples (Table 4). Taken together, the observed alterations in protein content in the thalassemic EVs are consistent with the known increase in oxidative burden due to peripheral hemolysis reported in previous studies, 13,22,24 and this study has substantially extended the number of known proteins with an altered concentration in HbE/ b-thalassemic patients' EVs.…”

Section: Discussionsupporting

confidence: 91%

“…These data 0.14 strengthen the hypothesis that the circulating plasma EVs are derived in part from erythrocyte lysis. 22 Finally, an increase in the quantity of cathepsin S, a potent elastolytic protease, was detected in thalassemic EVs, which may originate from activated myeloid cells. 23 Only 2 proteins, hemopexin and haptoglobin, were consistently and significantly reduced (12.5-to 25-fold and 7.1-to 20-fold reduction, respectively) in the patient compared with control EV samples across the 3 experiments (Table 3).…”

Section: Resultsmentioning

confidence: 97%

“…This is also consistent with the detection of RBC-specific proteins in EVs here by us and by other studies. 22 Chaperones are another group of proteins that exhibited an increased abundance in the patients' EVs. These proteins facilitate the refolding of damaged proteins resulting from oxidative stress in erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Several genotype-phenotype studies exploring the association between the AHSP gene and severity of thalassemia could not identify any correlation. [26][27][28] However, Bhattacharya et al 22 reported an increase of AHSP expression in thalassemic erythrocytes, which likely represents the original the source of AHSP for EVs.…”

Section: Discussionmentioning

confidence: 99%

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Quantitative proteomics of plasma vesicles identify novel biomarkers for hemoglobin E/β-thalassemic patients

et al. 2018

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Key Points• Chaperones, antioxidants, ironsequestering proteins, and cathepsin S exhibited increased abundance in thalassemic EVs.• Haptoglobin and hemopexin are reduced in thalassemic patients' EVs, reflecting hemolysis. These could be used as clinical biomarkers.Hemoglobin E (HbE)/b-thalassemia has a wide spectrum of clinical manifestations that cannot be explained purely by its genetic background. Circulating extracellular vesicles (EVs) are one factor that likely contributes to disease severity. This study has explored the differences in protein composition and quantity between EVs from HbE/b-thalassemic patients and healthy individuals. We used tandem mass tag labeling mass spectrometry to analyze the EV proteins isolated from the plasma of 15 patients compared with the controls.To reduce biological variation between individuals, the EV proteins isolated from randomly assigned groups of 5 HbE/b-thalassemic patients were pooled and compared with 5 pooled age-and sex-matched controls in 3 separate experiments. Alpha hemoglobin-stabilizing protein had the highest fold increase. Catalase, superoxide dismutase, T-complex proteins, heat shock proteins, transferrin receptor, ferritin, and cathepsin S were also upregulated in thalassemic circulating EVs. Importantly, haptoglobin and hemopexin were consistently reduced in patients' EVs across all data sets, in keeping with the existing hemolysis that occurs in thalassemia. The proteomic data analysis of EV samples isolated from 6 individual HbE/b-thalassemic patients and western blotting results corroborated these findings. In conclusion, we have successfully identified consistent alterations of protein quantity between EVs from HbE/b-thalassemic and healthy individuals. This work highlights haptoglobin, hemopexin, and cathepsin S as potential clinically relevant biomarkers for levels of hemolysis and inflammation. Monitoring of these plasma proteins could help in the clinical management of thalassemia.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Quantitative proteomics of plasma vesicles identify novel biomarkers for hemoglobin E/β-thalassemic patients

et al. 2018

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“…Severe patients, compared with mild patients, had an increase in markers of RBC oxidative stress based on ineffective erythropoiesis, lower RBC counts, PS exposure, greater serum EPO and plasma malondialdehyde (MDA), and RBC SOD. Other laboratories have shown not only an increase in RBC redox enzymes, such as PRDX2, catalase, thioredoxin, and SOD, but also an increase in the alpha globin chaperone, alpha hemoglobinstabilizing protein, negatively correlated with MCH and HbF (18,102,189).…”

Section: Fig 2 Hbe Acts As a Bmentioning

confidence: 96%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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Significance: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The b E -globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. Critical Issues: While HbE by itself presents as a mild anemia and a single gene for b-thalassemia is not serious, it remains unexplained why HbE/b-thalassemia (HbE/b-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/b-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess a-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. Future Directions: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26,[794][795][796][797][798][799][800][801][802][803][804][805][806][807][808][809][810][811][812][813]

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Pharmacoproteomics Profiling of Plasma From β‐Thalassemia Patients in Response to Hydroxyurea Treatment

Zohaib

Ansari

Shamsi

et al. 2018

The Journal of Clinical Pharma

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β-Thalassemia is a genetic disorder caused by defects in the β-globin gene resulting in the absence or reduced synthesis of adult hemoglobin (HbA). Hydroxyurea is an effective drug to increase fetal γ-globin (HbF) expression, replacing the missing adult β-globin. The mechanism of HbF induction by hydroxyurea and improvement in clinical symptoms are still poorly understood. In the present study we performed comparative analysis of plasma proteome in pre- and post-hydroxyurea-treated β-thalassemia major transfusion-dependent children (n = 10, mean age = 3.2 years) as well as responders versus nonresponders to hydroxyurea treatment. Plasma was collected before and after 6 months of hydroxyurea treatment, with patients subcategorized on the basis of their response to hydroxyurea. Among 400 identified proteins using a label-free quantitative proteomics approach, 28 proteins were found to be significantly different in pre- versus post-hydroxyurea-treated groups, with transferrin receptor protein-1 being most downregulated and hemopexin and haptoglobin the most upregulated proteins after treatment. In responder versus nonresponder comparison, 26 proteins were found to be differentially expressed, with carbonic anhydrase 1, hemoglobin subunit γ-1, and peroxiredoxin-2 showing the significant changes. The mechanism of hydroxyurea treatment in β-thalassemia patients appears to be complex, requiring a large sample size and a longer period of treatment to reveal its details.

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Differential regulation of redox proteins and chaperones in HbEβ‐thalassemia erythrocyte proteome

Cited by 41 publications

References 35 publications

Quantitative proteomics of plasma vesicles identify novel biomarkers for hemoglobin E/β-thalassemic patients

Quantitative proteomics of plasma vesicles identify novel biomarkers for hemoglobin E/β-thalassemic patients

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Pharmacoproteomics Profiling of Plasma From β‐Thalassemia Patients in Response to Hydroxyurea Treatment

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