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Lipid-free apolipoprotein A-I exerts an antioxidative role against cell-free hemoglobin.

ABSTRACT: Cell-free hemoglobin (Hb) resulting from hemolysis is redox-active. It disrupts the oxidoreducing microenvironment, shifting the balance unfavorably towards tissue cytotoxicity. Thus, immediate suppression of the Hb-redox activity and removal of the cell-free plasma Hb is vital for maintaining homeostasis and survival. Among several known Hb-binding plasma proteins, haptoglobin (Hp) is the primary antioxidant of Hb. However, Hb-mediated oxidative stress persists in the covalently bound Hb-Hp aggregates or when Hp is depleted during a severe hemolysis. We therefore inquired whether there is an alternative anti-oxidative defense tactic in the blood. Here, we identified an Hb-interactome in the plasma, constituting Hb, Hp and lipid-free apolipoprotein A-I (apoAI). We found that apoAI acts rapidly as a secondary antioxidant to interact with Hb and quench the Hb-redox activity. We showed that apoAI either acts independently or collaborates with Hp to downregulate Hb-redox activity. Following the association between apoAI and Hb, the apoAI facilitates the uptake of Hb by interacting with a scavenger receptor class B type 1 (SR-BI) displayed on macrophages and hepatocytes. Our findings suggest that apoAI mediates an efficient pathway for the elimination of cytotoxic Hb redox activity.

SUBMITTER: Du R

PROVIDER: S-EPMC3714184 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Lipid-free apolipoprotein A-I exerts an antioxidative role against cell-free hemoglobin.

Du Ruijuan R Winarsih Imelda I Ho Bow B Ding Jeak Ling JL

American journal of clinical and experimental immunology 20120530 1

Cell-free hemoglobin (Hb) resulting from hemolysis is redox-active. It disrupts the oxidoreducing microenvironment, shifting the balance unfavorably towards tissue cytotoxicity. Thus, immediate suppression of the Hb-redox activity and removal of the cell-free plasma Hb is vital for maintaining homeostasis and survival. Among several known Hb-binding plasma proteins, haptoglobin (Hp) is the primary antioxidant of Hb. However, Hb-mediated oxidative stress persists in the covalently bound Hb-Hp agg ...[more]

PMID: 23885313

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Project description:Intravascular hemolysis and hemoglobinuria are associated with sickle cell nephropathy. ApoL1 is involved in cell-free hemoglobin scavenging through association with haptoglobin-related protein. APOL1 G1/G2 variants are the strongest genetic predictors of kidney disease in the general African-American population. A single report associated APOL1 G1/G2 with sickle cell nephropathy. In 221 patients with sickle cell disease at the University of Illinois at Chicago, we replicated the finding of an association of APOL1 G1/G2 with proteinuria, specifically with urine albumin concentration (?=1.1, P=0.003), observed an even stronger association with hemoglobinuria (OR=2.5, P=4.3×10(-6)), and also replicated the finding of an association with hemoglobinuria in 487 patients from the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy study (OR=2.6, P=0.003). In 25 University of Illinois sickle cell disease patients, concentrations of urine kidney injury molecule-1 correlated with urine cell-free hemoglobin concentrations (r=0.59, P=0.002). Exposing human proximal tubular cells to increasing cell-free hemoglobin led to increasing concentrations of supernatant kidney injury molecule-1 (P=0.01), reduced viability (P=0.01) and induction of HMOX1 and SOD2. HMOX1 rs743811 associated with chronic kidney disease stage (OR=3.0, P=0.0001) in the University of Illinois cohort and end-stage renal disease (OR=10.0, P=0.0003) in the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy cohort. Longer HMOX1 GT-tandem repeats (>25) were associated with lower estimated glomerular filtration rate in the University of Illinois cohort (P=0.01). Our findings point to an association of APOL1 G1/G2 with kidney disease in sickle cell disease, possibly through increased risk of hemoglobinuria, and associations of HMOX1 variants with kidney disease, possibly through reduced protection of the kidney from hemoglobin-mediated toxicity.

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Lipid-free apolipoprotein A-I exerts an antioxidative role against cell-free hemoglobin.

Publications

Lipid-free apolipoprotein A-I exerts an antioxidative role against cell-free hemoglobin.

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