P57: HbE/β-thalassemia associated pathophysiology: Mechanisms originating from reduced HbE nitrite reactivity

Abstract

HbE/β-thalassemia (HbE/β-thal) is probably the most common severe hemoglobinopathy world-wide: a heterogenous clinical spectrum presents with variations in anemia, growth, development, hepatosplenomegaly, and transfusion requirements. Hence, HbE/β-thal is a serious cause of chronic disease resulting in high morbidity with often fatal consequences from cardiac failure. It is most prevalent in Southeast Asia but is now a national health issue, encountered with increasing frequency in immigrants living in the United States, as well as Canada, Europe, and Australia. Mutant HbE exhibits normal oxygen affinity and cooperativity, and an enhanced redox potential. Homozygous individuals (HbEE) manifest only a mild, chronic anemia and individuals with β-thal trait usually exhibit a benign clinical picture. Thus, it remains an enigma as to why HbE/β-thal individuals exhibit high morbidity that often results in death by cardiac failure. The pathology has been attributed to the mild thalassemic-like nature of the HbE mutation at the α1β1 interface and coupling with β-thal that causes significant oxidative stress. While HbE in vitro is highly unstable, no in vivo evidence for HbE instability has been demonstrated. A plausible mechanism directly related to the functional properties of HbE has yet to emerge. We have uncovered in vitro a surprising functional difference of purified HbE compared to normal HbA: despite very similar oxygen binding properties, HbE exhibits reduced efficacy as a nitrite-mediated generator of nitric oxide [i.e., minimized nitrite reductase (NR) activity] [Roche et al., J. Biol. Chem., 2011]; and recently, demonstrated that HbE is inefficient in the nitrite anhydrase (NA) reaction, while enhanced in the reductive nitrosylation (RN) reaction]. Sol–gel studies support a mechanism whereby the R/T dependent redox potential is the primary factor controlling the partitioning between the RN and NA reactions of Hb. These observations have led to a hypothesis that provides a novel explanation for HbE/β-thal pathophysiology: since HbE in vitro exhibits decreased NR and NA activity, and is enhanced in the RN reaction compared to normal HbA, the pathology associated with HbE/β-thal disease arises from the decreased bioavailability of nitric oxide that in turn exacerbates a mild oxidative stress arising from β-thal trait, that in sum, engenders deleterious consequences, both at the level of the RBC and vasculature. These novel findings and model will be presented in an overview of this grave disease. Nothing to disclose.