Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice
Samit Ghosh, Chibueze A. Ihunnah, Rimi Hazra, Aisha L. Walker, Jason M. Hansen, David R. Archer, Amma T. Owusu-Ansah, Solomon F. Ofori-Acquah
Samit Ghosh, Chibueze A. Ihunnah, Rimi Hazra, Aisha L. Walker, Jason M. Hansen, David R. Archer, Amma T. Owusu-Ansah, Solomon F. Ofori-Acquah
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Research Article Hematology Vascular biology

Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice

Abstract

The prevention of organ damage and early death in young adults is a major clinical concern in sickle cell disease (SCD). However, mechanisms that control adult progression of SCD during the transition from adolescence are poorly defined with no cognate prophylaxis. Here, we demonstrate in a longitudinal cohort of homozygous SCD (SS) mice a link between intravascular hemolysis, vascular inflammation, lung injury, and early death. Prophylactic Nrf2 activation in young SS mice stabilized intravascular hemolysis, reversed vascular inflammation, and attenuated lung edema in adulthood. Enhanced Nrf2 activation in endothelial cells in vitro concurred with the dramatic effect on vascular inflammation in the mice. BM chimeric SS mice lacking Nrf2 expression in nonhematopoietic tissues were created to dissect the role of nonerythroid Nrf2 in SCD progression. The SS chimeras developed severe intravascular hemolysis despite having erythroid Nrf2. In addition, they developed premature vascular inflammation and pulmonary edema and died younger than donor littermates with intact nonhematopoietic Nrf2. Our results reveal a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD. Furthermore, we show that prophylactic augmentation of Nrf2-coordinated cytoprotection effectively impedes onset of the severe adult phenotype of SCD in mice.

Authors

Samit Ghosh, Chibueze A. Ihunnah, Rimi Hazra, Aisha L. Walker, Jason M. Hansen, David R. Archer, Amma T. Owusu-Ansah, Solomon F. Ofori-Acquah

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Figure 2

Hemolytic stress, vascular inflammation, and lung injury deteriorate with aging in sickle mice.

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Hemolytic stress, vascular inflammation, and lung injury deteriorate wit...
(A) Extremely low hemopexin level in 1-month-old transgenic sickle (SS) mice (n = 8–14) followed by declining values thereafter. By contrast plasma hemopexin (plasma Hx) level rises steadily in the maturing control (AA) mice (n = 14) and plateaus at a high value in adulthood (***P < 0.001 using t test between 1 and 2 months). (B) Developmentally stable plasma haptoglobin (plasma Hp) level in both SS and AA mice (n = 8–14). (C) Progressive increases in percent methemoglobin (metHb) in SS but not in AA mice. (D) Plasma heme oxygense-1 (HO-1) level in 1-month SS mice is markedly high and drops to a stable value thereafter. The HO-1 level in AA mice is lower than in SS at all stages of maturation (n = 10). *P < 0.05 comparing HO-1 level in SS between 1 and 2 months using t test; #P < 0.001 showing difference in plasma HO-1 concentration of AA and SS mice at different ages, unpaired t test. (E) The concentration of soluble vascular cell adhesion molecule (sVCAM-1), a marker of endothelial injury in plasma, increases steadily in the SS but not in the AA mice with aging (n = 6–9). (F) Concentration of soluble vascular endothelial cadherin (sVE-cadherin) is also similar at 1 month in both groups of mice but rises steadily in the SS mice and reaches a significantly elevated level at 3 months (n = 6). *P < 0.05 and ***P < 0.001, indicating statistical differences (ANOVA) between SS mice 1–10 month of age. (G) Representative H&E-stained lung tissue sections of SS and AA mice at 1–10 months of age (×10). Higher magnification (×40) of the 10-month-old lung section for indicated area features alveolar wall thickening and edema in SS mice. Original magnification ×100 and ×400.