Abstract 13106: Over Expression of Glyoxalase 1 Prevents Chronic Hyperglycemia Induced Explant Derived Cardiac Stem Cell Dysfunction
Diabetes increases the risk of heart disease and worsens clinical outcomes after myocardial infarction. Given that hyperglycemia promotes the generation of toxic methylglyoxal, the influence of the key detoxification enzyme glyoxalase 1 (Glo1) on chronic hyperglycemia induced explant-derived cardiac stem cell (EDC) dysfunction was investigated.
Methods/Results: Sixteen-week old wild type (WT, n=22) or constitutive Glo1 overexpressing (Glo1TG, n=12) mice were studied 2 months after treatment with streptozotocin or vehicle (2.0±0.1 fold increase in glycated hemoglobin, p=0.001 vs vehicle treated mice). Hyperglycemia reduced overall culture yields (86±3% fewer EDCs cultured, p=0.0009) and prolonged population doubling time (30±4% slower growth, p=0.04) while increasing the cellular content of reactive dicarbonyls (27±3% more reactive oxygen species, p=0.0006) within EDCs cultured from WT mice. These intrinsic cell changes reduced the angiogenic potential (74±2% less total endothelial tubule formation, p=0.001) and production of pro-healing exosomes (43±6% fewer exosomes secreted, p=0.04) by hyperglycemic EDCs while promoting EDC senescence (98±28% more senescent EDCs, p=0.03). As compared to transplant of normoglycemic WT EDCs, hyperglycemia reduced the EDC-mediated increases in echocardiographic ejection fraction and dP/dTmax in infarcted normoglycemic WT mice 3 weeks after intra-myocardial injection by 37±8% (p=0.0001) and 25±1% (p=0.001), respectively. In contrast to EDCs cultured from WT hyperglycemic donors, EDCs cultured from Glo1TG mice: 1) decreased the reactive oxygen species content by 46±2% (p=0.0001), 2) increased cell culture yields by 2.2±0.2 fold (p=0.0004) and 3) boosted echocardiographic left ventricular ejection fraction by 27±7% (p=0.0001) while increasing dP/dTmax by 21±4% (p=0.007).
Conclusions: Chronic hyperglycemia decreases the regenerative performance of EDCs. Over-expression of Glo1 reduces dicarbonyl stress and prevents chronic hyperglycemia-induced EDC dysfunction.
Author Disclosures: M. Villanueva: None. D.R. Davis: None.
- © 2016 by American Heart Association, Inc.