STIMULATION OF ANGIOGENESIS AND THE GENERATION OF NEW CARDIOMYOCYTES UNDERLIE THERAPEUTIC REGENERATION BY EXPLANT-DERIVED CARDIAC STEM CELLS FROM HYPERGLYCEMIC DONORS GENETICALLY PROGRAMMED TO OVER-EXPRESS GLYOXALASE 1

Chronic hyperglycemia promotes the generation of toxic methylglyoxal. Previously, we have shown that elevated dicarbonyl stress within ex vivo proliferated explant-derived cardiac stem cells (EDCs) reduces cell-mediated repair of injured myocardium and that over-expression of the key detoxification enzyme glyoxalase 1 (Glo1) within hyperglycemic hosts attenuated the adverse effects of hyperglycemia. Here, we explore the fundamental mechanisms underlying these benefits. A series of 16-week old wild type (WT) or Glo1 overexpressing (Glo1TG) mice were studied 2 months after treatment with streptozotocin or vehicle (2.0±0.1-fold increase in Hb1Ac, p=0.001 vs vehicle treated mice). Myocardial infarction was induced in female C57BL/6 mice by permanent left coronary ligation followed 1 week later by randomization to echocardiographic guided intra-myocardial injection of hyperglycemic male WT or Glo1TG EDCs. Histological analysis revealed that transplant of WT EDCs from hyperglycemic hosts reduced myocardial vessel density (52±19% fewer isolectin b4+ vessels, p=0.008) while increasing overall scar burden (53±21% greater scar burden, p=0.002). BrdU pulsing for 1 week after injection of hyperglycemic WT EDCs demonstrated that exposure to chronic hyperglycemia reduced the ability of EDCs to promote the generation of new myocytes (BrdU+/cTnT+) in the peri-infarct border zone by 54±22% (p=0.01) as compared to normoglycemic EDCs. In contrast, over-expression of Glo1 protected EDCs from the effects of hyperglycemia and restored the ability of EDCs to promote new vessel growth (90±57% more isolectin b4+ vessels, p=0.05), reduce infarct size (36±12% less scar burden, p=0.02) and generate new myocytes in the peri-infarct border zone (89±33% more myocytes; p=0.01). Over-expression of Glo1 attenuates the adverse effects of hyperglycemia to boost therapeutic regeneration through stimulation of angiogenesis and the generation of new cardiomyocytes.