Stimulation of Suicidal Erythrocyte Death by Methylglyoxal

Abstract

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 Ca²⁺-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 µM) encountered in diabetic patients. Surprisingly, methylglyoxal did not significantly increase cytosolic Ca²⁺ concentration, and at concentrations up to 3 µM, 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.

Hemin-induced suicidal erythrocyte death

“…Some of these diseases may cause eryptosis by stimulating the formation of hemin. Furthermore, several eryptosis-triggering xenobiotics and endogeneous substances have been identified, such as cordycepin [50], methylglyoxal [54], amyloid peptides [53], lipopetides [71] retinoic acid [55], paclitaxel [44], amantadine [23], chlorpromazine [1], ciglitazone [58], cyclosporine [56], Bay-5884 [65], curcumin [4], valinomycin [64], listeriolysin [25], aluminum [57], copper [46], bismuth [13], tin [52], cadmium [68], selenium [67], vanadate [27], gold [69], and arsenic [51]. At least in theory, some of those substances may be effective through stimulation of hemin formation.…”

Erythrocyte programmed cell death

“…Suicidal erythrocyte death could be triggered by ligation of specific surface antigens, such as glycophorin-C (41), the thrombospondin-1 receptor CD47 (42) and the death receptor CD95/Fas (43). Further stimulators of eryptosis include ceramide (acylsphingosine) (44), prostaglandin E 2 (45), platelet activating factor (46), anti A IgG antibodies (47), hemolysin from Vibrio parahaemolyticus (48), listeriolysin (49), paclitaxel (50), amantadine (51), azathioprine (52), retinoic acid (53), chlorpromazine (54), cyclosporine (55), methylglyoxal (56), amyloid peptides (57), anandamide (58), Bay-Y5884 (59), curcumin (60), valinomycin (61), aluminium (62), mercury (63), lead (64), gold (65), vanadium (66) and copper (67).…”

“…Eryptosis could be triggered by increase in the cytosolic Ca 21 activity, which leads to cell membrane vesiculation (68) and stimulates cell membrane scrambling resulting in phosphatidylserine exposure at the cell surface (54)(55)(56). Ca 21 further stimulates the cysteine endopeptidase calpain, which degrades the cytoskeleton and thus facilitates cell membrane blebbing (69) (Fig.…”

Anemia and splenomegaly in cGKI-deficient mice

“…A decrease of NO-dependent activation of cGKI could participate in the pathophysiology of those conditions. Moreover, accelerated eryptosis participates in the pathophysiology of iron deficiency (32), hemolytic uremic syndrome (49), sepsis (50), malaria (51), Wilson's disease (52), thalassemia (53), glucose-phosphate dehydrogenase deficiency (53), and diabetes (54). At least in theory, stimulation of cGKI could reverse accelerated eryptosis in those diseases.…”