Ameliorating Methylglyoxal-Induced Progenitor Cell Dysfunction for Tissue Repair in Diabetes

Abstract

Patient-derived progenitor cell (PC) dysfunction is severely impaired in diabetes, but the molecular triggers that contribute to mechanisms of PC dysfunction are not fully understood. Methylglyoxal (MGO) is one of the highly reactive dicarbonyl species formed during hyperglycemia. We hypothesized that the MGO scavenger glyoxalase 1 (GLO1) reverses bone marrow-derived PC (BMPC) dysfunction through augmenting the activity of an important endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), resulting in improved diabetic wound healing. BMPCs were isolated from adult male db/db type 2 diabetic mice and their healthy corresponding control db/+ mice. MGO at the concentration of 10 µmol/L induced immediate and severe BMPC dysfunction, including impaired network formation, migration, and proliferation and increased apoptosis, which were rescued by adenovirus-mediated GLO1 overexpression. IRE1α expression and activation in BMPCs were significantly attenuated by MGO exposure but rescued by GLO1 overexpression. MGO can diminish IRE1α RNase activity by directly binding to IRE1α in vitro. In a diabetic mouse cutaneous wound model in vivo, cell therapies using diabetic cells with GLO1 overexpression remarkably accelerated wound closure by enhancing angiogenesis compared with diabetic control cell therapy. Augmenting tissue GLO1 expression by adenovirus-mediated gene transfer or with the small-molecule inducer trans-resveratrol and hesperetin formulation also improved wound closure and angiogenesis in diabetic mice. In conclusion, our data suggest that GLO1 rescues BMPC dysfunction and facilitates wound healing in diabetic animals, at least partly through preventing MGO-induced impairment of IRE1α expression and activity. Our results provide important knowledge for the development of novel therapeutic approaches targeting MGO to improve PC-mediated angiogenesis and tissue repair in diabetes.

SIRT1-Dependent Upregulation of Antiglycative Defense in HUVECs Is Essential for Resveratrol Protection against High Glucose Stress

“…In particular, the ability of RSV to protect endothelial cells, not just because of its unspecific direct antioxidant properties, but through the activation of the SIRT1-GLO1 pathway, may be of great relevance. In fact, many experimental and clinical studies confirmed that GLO1 inducers and/or dicarbonyl scavengers represent potential effective agents to reverse or limit diabetes-related complications [70,91,92,93,94].…”

Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging

“…The suggestion deriving from the existent studies is that the dysregulation of VEGF action by dicarbonyl stress sustains aberrant angiogenesis. In line with this, the overexpression of Glo1 inhibits AGEs formation in ECs [133], favors both angiogenesis in vitro [134] and in vivo facilitating wound healing [135] and muscle reperfusion after ischemic insults in diabetic rats [136]. Our group has recently identified the antiangiogenic factor Homeobox A5 (HoxA5) as a new player in MGO-induced angiogenesis impairment of ECs knock-down for Glo1.…”

Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer

“…PDLFs were relatively resistant to toxicity induced by exogenous MG: incubation of PLDFs with 25-1000 µM for 2 days produced growth arrest and toxicity at ≥200 µM MG-a concentration profoundly greater than physiological extracellular concentrations of MG. The median growth inhibitory concentration GC 50 Pathophysiology/complications flux of glucose consumption by PDLFs ( figure 2G). There was no net increase in formation of L-lactate ( figure 2H).…”

“…This involved correction of the UPR stress sensor of the ER, inositol requiring enzyme 1α. 50 tRES-HESP was optimized for induction of expression of Glo1 by activation of Nrf2 with median effective concentration EC 50 of 1.46 µM. 19 Other Nrf2-regulated genes are implicated in the prevention of metabolic dysfunction induced by HG concentration in PDLFs in culture: increased expression of G6PD (see above) and γ-glutamylcysteine ligase, catalytic and modifier subunits (γ-glutamylcysteine ligase and γglutamylcysteineligase, modifier subunit)-likely mediating the increase in cellular GSH in both LG and HG concentration cultures.…”