Stimulation of suicidal erythrocyte death by methylglyoxal.
Diabetes increases the percentage of circulating erythrocytes exposing phosphatidylserine (PS) at the cell surface. PS-exposing erythrocytes are recognized, bound, engulfed and degraded by macrophages. Thus, PS exposure, a feature of suicidal erythrocyte death or eryptosis, accelerates clearance of affected erythrocytes from circulating blood. Moreover, PS-exposing erythrocytes bind to the vascular wall thus interfering with microcirculation. The present study explored mechanisms involved in the triggering of PS exposure by methylgloxal, an extra- and intracellular metabolite which is enhanced in diabetes. PS exposure, cell size and cytosolic Ca(2+)-activity after methylglyoxal treatment were measured by FACS analysis of annexin V binding, forward scatter and Fluo-3-fluorescence, respectively, and it was shown that the treatment significantly enhanced the percentage of PS-exposing erythrocytes at concentrations (0.3 microM) encountered in diabetic patients. Surprisingly, methylglyoxal did not significantly increase cytosolic Ca(2+) concentration, and at concentrations up to 3 microM, did not decrease the forward scatter. Instead, exposure to methylglyoxal inhibited glycolysis thus decreasing ATP and GSH concentrations. In conclusion, methylglyoxal impairs energy production and anti-oxidative defense, effects contributing to the enhanced PS exposure of circulating erythrocytes and eventually resulting in anemia and deranged microcirculation.
Nicolay
Jan P
JP
Department of Physiology, University of Tübingen, Tübingen, Germany.
Schneider
Juliane
J
Niemoeller
Olivier M
OM
Artunc
Ferruh
F
Portero-Otin
Manuel
M
Haik
George
G
Thornalley
Paul J
PJ
Schleicher
Erwin
E
Wieder
Thomas
T
Lang
Florian
F
D017304:Annexin A5 / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D016923:Cell Death; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000150:complications; D004912:Erythrocytes / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D010718:Phosphatidylserines / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000097:blood / Q000633:toxicity*
D017304:Annexin A5; D001786:Blood Glucose; D010718:Phosphatidylserines; D011765:Pyruvaldehyde