Mechanisms of NRF2 activation to mediate fetal hemoglobin induction and protection against oxidative stress in sickle cell disease

Abstract

Individuals with sickle cell disease have severe anemia due to the production of abnormal hemoglobin S, chronic red blood cell hemolysis, and increased oxidative stress leading to endothelial cell dysfunction, vasculopathy, and progressive organ damage. The transcription factor NRF2 (erythroid-derived 2)-like 2) is a master regulator of antioxidant proteins; under low oxidative stress, NRF2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1, β-transducin repeat-containing protein or HRD1, and directed to the proteasome for degradation. When cells are exposed to oxidative stress, NRF2 is released from these repressor proteins, translocates to the nucleus, and activates antioxidant genes to suppress cellular reactive oxidant species and inflammation. In erythroid progenitors, NRF2 also modulates fetal hemoglobin expression through direct binding in the γ-globin promoter and modification of chromatin structure in the β-globin locus. In sickle erythroid cells, NRF2 provides unique benefits through fetal hemoglobin induction to inhibit hemoglobin S polymerization and protection against oxidative stress due to chronic hemolysis. Thus, development of small chemical molecules that activate NRF2 has the potential to ameliorate the clinical severity of sickle cell disease. In this review, we discuss progress towards understanding NRF2 regulation and strategies to develop agents for the treatment of sickle cell disease. Impact statement Sickle cell disease (SCD) is a group of inherited blood disorders caused by mutations in the human β-globin gene, leading to the synthesis of abnormal hemoglobin S, chronic hemolysis, and oxidative stress. Inhibition of hemoglobin S polymerization by fetal hemoglobin holds the greatest promise for treating SCD. The transcription factor NRF2, is the master regulator of the cellular oxidative stress response and activator of fetal hemoglobin expression. In animal models, various small chemical molecules activate NRF2 and ameliorate the pathophysiology of SCD. This review discusses the mechanisms of NRF2 regulation and therapeutic strategies of NRF2 activation to design the treatment options for individuals with SCD.

Selenium Status and Hemolysis in Sickle Cell Disease Patients

“…It is known, however, that the nuclear factor E2-related factor 2 (Nrf2) is a key transcription factor binding to the antioxidant response elements (ARE) present in the promoter regions of various antioxidant enzymes. In selenium deficiency, Nrf2 expression is increased, as a compensatory mechanism [33,35]. In sickle erythroid cells, Nrf2 induces HbF synthesis in order to inhibit hemoglobin S polymerization and protect against oxidative stress due to chronic hemolysis [35].…”

“…In selenium deficiency, Nrf2 expression is increased, as a compensatory mechanism [33,35]. In sickle erythroid cells, Nrf2 induces HbF synthesis in order to inhibit hemoglobin S polymerization and protect against oxidative stress due to chronic hemolysis [35]. This may explain the inverse relationship between selenium and HbF, shown in Table 4.…”

Redox signaling in sickle cell disease

“…Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that protects cells from oxidative damage by promoting the expression of a wide variety of antioxidants (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Kelch-like ECH-associated protein 1 (Keap1) regulates Nrf2 activity (20,23,24). Under normal physiological conditions, Keap1 sequesters Nrf2, which is then ubiquitinated by cullin-3 containing ubiquitin ligase and degraded.…”

Relationship between oxidative stress and nuclear factor‑erythroid‑2‑related factor 2 signaling in diabetic cardiomyopathy (Review)

“…These stresses can alter the microvascular structure and ventricular dilation, ultimately leading to cardiac dysfunction and HF ( 12 , 38 ). However, it is common that the heart remains within the normal range of ejection fraction ( 72 ).…”