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Glyoxalase 1 Prevents Chronic Hyperglycemia Induced Heart-Explant Derived Cell Dysfunction

Melanie Villanueva1, Connor Michie1, Sandrine Parent1

  • 1University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, Canada K1Y4W7.

Theranostics
|September 20, 2019
PubMed

Insights

Diabetes impairs heart cell therapy by increasing toxic metabolites. Overexpressing the glyoxalase 1 (Glo1) enzyme reduces this damage, improving cell function and heart repair in diabetic conditions.

Area of Science:

  • Cardiovascular Research
  • Metabolic Disease Research
  • Regenerative Medicine

Background:

  • Diabetes significantly increases heart disease risk and worsens outcomes post-myocardial infarction.
  • Cell therapy is a promising alternative for heart repair in diabetic patients, as heart transplantation is contraindicated.
  • Hyperglycemia in diabetes generates toxic metabolites, impairing cell function.

Purpose of the Study:

  • To investigate the role of glyoxalase 1 (Glo1) in mitigating hyperglycemia-induced dysfunction of heart explant-derived cells (EDCs).
  • To evaluate the therapeutic potential of Glo1-overexpressing EDCs in models of myocardial ischemia.

Main Methods:

  • EDCs were cultured from mice treated with streptozotocin (to induce hyperglycemia) or vehicle, including Glo1 over-expressing and wild-type groups.
  • In vitro and in vivo models of myocardial ischemia were used to assess EDC function and therapeutic efficacy.
  • Evaluated cell culture yields, dicarbonyl stress, angiogenic potential, exosome production, senescence, proliferation, and cardiac function post-transplantation.

Main Results:

  • Chronic hyperglycemia reduced EDC culture yields, increased dicarbonyl stress, and impaired angiogenic potential and exosome production.
  • Hyperglycemic EDCs showed reduced efficacy in improving myocardial function and promoting vascular/cardiomyocyte growth compared to normoglycemic cells.
  • Glo1 overexpression restored EDC culture yields and improved repair of ischemic myocardium, associated with enhanced extracellular vesicle production.

Conclusions:

  • Chronic hyperglycemia impairs the regenerative capacity of EDCs, negatively impacting their therapeutic potential for heart repair.
  • Glyoxalase 1 (Glo1) overexpression mitigates dicarbonyl stress and prevents hyperglycemia-induced EDC dysfunction.
  • Restoring Glo1 levels rejuvenates EDC function by enhancing pro-healing extracellular vesicle production, offering a potential therapeutic strategy for diabetic heart disease.

Keywords:
cardiac stem cellsdiabetesextracellular vesiclesheart failurehyperglycemiamyocardial infarctionoxidative stressreactive dicarbonyls

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