Abstract 1672: Persistence of Endothelial Dysfunction as a Marker of Metabolic Memory in Diabetic Mice after Glucose Normalization
Background. The concept that hyperglycemia has long-lasting effects that perpetuate vascular damage, even after blood glucose normalization, has recently emerged and defined as “metabolic memory”. Reactive oxygen species (ROS) may be involved in this phenomenon. Genetic deletion of p66Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. The present study was designed to investigate the effects of tight blood glucose control on endothelial dysfunction and oxidative stress in diabetic p66Shc-/-and wild type (WT) mice.
Methods and Results. Four weeks after the induction of diabetes by a single i.p. injection of streptozotocin (STZ, 200 mg/Kg), both p66Shc-/- and WT mice received subcutaneous administration of sustained release insulin implants (Linshin Inc, Ontario, Canada). After two weeks, treated and untreated mice were euthanized, and the aorta was excised, stored at -80°C, or used immediately for organ chamber experiments. STZ-treated p66Shc-/- and WT mice showed similar increase in blood glucose (102 ± 2 vs 519 ± 32 mg/dl and 106 ± 4 vs 431 ± 38 mg/dl, respectively) which was restored to normal values by insulin (123 ± 22 and 138 ± 15 mg/dl, respectively; p = NS vs baseline). However, significant differences arose with respect to endothelial dysfunction and oxidative stress. In spite of glucose normalization, WT diabetic mice displayed persistent impairment of endothelium-dependent relaxation to acetylcholine (10–9 –10–5 mol/L) and increased aortic nitrotyrosine expression (n = 6 in each group, p < 0.05 vs p66Shc-/- treated mice).
Conclusions. Oxidative stress-resistant p66Shc-/- mice do not develop metabolic memory. These results indicate that hyperglycemia-induced ROS generation plays a crucial role in triggering persistence of vascular dysfunction after blood glucose normalization. Our study provides molecular insights for understanding the progression of diabetic complications despite tight metabolic control.