Abstract 1905: Restoration of Normoglycemia Re-Establishes the Infarct-Sparing Effect of Postconditioning in Diabetic Mice

Abstract

Relief of ischemia in a stuttering manner (postconditioning: PostC) reduces infarct size in healthy adult populations, due in part to activation of ERK 1/2 during the early minutes of reflow. However, emerging evidence suggests that PostC fails to limit ischemia-reperfusion injury in the setting of diabetes. Our current aim was to establish whether this loss in efficacy of PostC reflects a permanent diabetes-associated defect in cardioprotective signaling, or whether therapy to restore normoglycemia can re-establish the PostC phenotype. To address this issue, isolated buffer-perfused hearts were obtained from 4 cohorts of C57BL/6J mice: healthy adults; animals injected 2 or 4 wks earlier with streptozotocin (STZ) to induce diabetes; and mice injected 4 wks earlier with STZ that, at 2 wks after being rendered diabetic, received islet cell transplantation (ICT). All hearts underwent 30 min global ischemia and, within each cohort, were assigned to receive either complete, abrupt reperfusion (controls) or PostC with 3 10-sec cycles of stuttered reflow. In hearts from healthy mice: (i) PostC was cardioprotective (infarct size [delineated by tetrazolium staining] was 27±3% vs 50±3% of the LV in PostC hearts vs controls; p<.05); (ii) PostC-induced protection was associated with significant, >2-fold increases in expression of phospho-MEK, phospho-ERK and downstream targets of ERK; and (iii) the benefits of PostC were abrogated by the MEK inhibitor PD98059. At both 2 and 4 weeks post-STZ injection, mice displayed: (i) low plasma insulin levels (0.18±0.08 and 0.07±0.02 vs 1.40±0.20 ng/ml) and hyperglycemia (blood glucose: 556±15 and 558±10 vs 178±7 mg/dl in healthy C57 mice); (ii) no up-regulation of ERK signaling in response to stuttered reflow; and (iii) no infarct-sparing effect of PostC (mean infarct sizes: 62– 63% in STZ-PostC groups vs 58 – 63% in STZ-controls). In contrast, ICT: (i) restored normal insulin and blood glucose levels (1.33±0.09 ng/ml; 189±7 mg/dl) and, most notably (ii) reinstated the up-regulation in ERK signaling and infarct-sparing effect of PostC (infarct size: 31±3% vs 51±5% in STZ±ICT controls; p<0.05). Thus, therapeutic control of insulin and blood glucose re-establishes the protective PostC phenotype in this mouse model of diabetes.