Oxidative red blood cell membrane injury in the pathophysiology of severe
mouse beta-thalassemia
R Advani, E Rubin, N Mohandas and SL Schrier
Department of Medicine (Hematology), Stanford University Medical School, CA
94305-5112.
In severe human beta-thalassemia, the pathophysiology relates to
accumulation of excess alpha-globin chains at the membrane. One hypothesis
is that membrane-associated alpha-globin by virtue of it's iron or
hemichromes produces oxidation of adjacent membrane proteins. The
availability of a mouse model of severe beta-thalassemia, as well as a
transgenic (thalassemic-sickle) mouse that expresses 12% of human beta
s-chain, has allowed us to study the effect of graded accumulation of
alpha-chains at the red blood cell (RBC) membrane on the clinical status of
the animal and on the material properties of its RBCs. Proteins from
control, beta-thalassemic, and transgenic mouse RBC membranes were analyzed
for evidence of oxidation, as measured by thiol- disulfide exchange
chromatography, which detects intramolecular sulfhydryl oxidation. Ratios
of oxidized globin to protein 7 were calculated and increased amounts were
seen in thalassemic mice as compared with control mice and transgenic mice.
Furthermore, there were increased amounts of thiol-free protein 4.1 in the
thalassemic mice, compared with very small amounts in the control mice and
intermediate amounts in the transgenic mice. Membrane mechanical stability
as assessed by ektacytometry showed that the thalassemic mouse RBCs were
markedly unstable. Transgenic mouse RBCs showed intermediate levels of
membrane instability compared with the controls. We propose that this
oxidized globin, in conjunction with oxidized protein 4.1, accounts (at
least in part) for membrane instability. A 12% increase in beta s- globin
chain synthesis (by decreasing excess globin available) confers
considerable protection against both oxidative damage and the consequent
membrane instability.
Volume 79,
Issue 4,
pp. 1064-1067,
02/15/1992
Copyright © 1992 by The American Society of Hematology
