Details

Autor(en) / Beteiligte

• Rogers, Stephen C
• Said, Ahmed
• Corcuera, Daniella
• McLaughlin, Dylan
• Kell, Pamela
• Doctor, Allan

Titel

Hypoxia limits antioxidant capacity in red blood cells by altering glycolytic pathway dominance

Ist Teil von

• The FASEB journal, 2009-09, Vol.23 (9), p.3159-3170

Ort / Verlag

United States: The Federation of American Societies for Experimental Biology

Erscheinungsjahr

2009

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• The erythrocyte membrane is a newly appreciated platform for thiol-based circulatory signaling, and it requires robust free thiol maintenance. We sought to define physiological constraints on erythrocyte antioxidant defense. Hemoglobin (Hb) conformation gates glycolytic flux through the hexose monophosphate pathway (HMP), the sole source of nicotinamide adenine dinucleotide phosphate (NADPH) in erythrocytes. We hypothesized elevated intraerythrocytic deoxyHb would limit resilience to oxidative stress. Human erythrocytes were subjected to controlled oxidant (superoxide) loading following independent manipulation of oxygen tension, Hb conformation, and glycolytic pathway dominance. Sufficiency of antioxidant defense was determined by serial quantification of GSH, NADPH, NADH redox couples. Hypoxic erythrocytes demonstrated greater loss of reduction potential [Δ GSH Ehc (mV): 123.4±9.7 vs. 57.2±11.1] and reduced membrane thiol (47.7±5.7 vs. 20.1±4.3%) (hypoxia vs. normoxia, respectively; P<0.01), a finding mimicked in normoxic erythrocytes after HMP blockade. Rebalancing HMP flux during hypoxia restored resilience to oxidative stress at all stages of the system. Cell-free studies assured oxidative loading was not altered by oxygen tension, heme ligation, or the inhibitors employed. These data indicate that Hb conformation controls coupled glucose and thiol metabolism in erythrocytes, and implicate hypoxemia in the pathobiology of erythrocyte-based vascular signaling.--Rogers, S. C., Said, A., Corcuera, D., McLaughlin, D., Kell, P., Doctor, A. Hypoxia limits antioxidant capacity in red blood cells by altering glycolytic pathway dominance.