Abstract 546: Postconditioning Fails to Limit Infarct Size in the Setting of Type-2 and Type-1 Diabetes
Relief of ischemia in a stuttering manner (postconditioning: PostC) has been shown to limit infarct size, due in part to activation of ERK 1/2 during the early minutes of reflow. However, it is unknown whether the efficacy of PostC is maintained in the setting of clinically relevant co-morbidities such as diabetes. To address this issue, isolated buffer-perfused hearts were obtained from:
healthy adult C57BL/6J mice (mean blood glucose [mg/dL]: 178±7);
age-matched BKS.Cg-m+/+Leprdb/J mice (genetic model model of type-2 diabetes; hyper-glycemic with blood glucose of 480±23); and
adult C57 mice injected 2 weeks previously with streptozotocin (model of type-1 diabetes; blood glucose: 556±15).
All hearts underwent 30 min global ischemia and received either:
complete, abrupt reperfusion (controls);
PostC with 3 10-sec cycles of stuttered reflow; or
an amplified (6 cycle) PostC stimulus.
Experiments were conducted with both standard perfusate and fatty acid-supplemented buffer (1.5 mM palmitate). In hearts from healthy mice, PostC:
was cardioprotective (infarct size [delineated by tetrazolium staining] was 27±3% and 29±5% of the LV in PostC groups vs 50±3% in controls; p<.05); and
was associated with an up-regulation of ERK signaling (including significant, >2-fold increases in expression of phospho-ERK and downstream targets of ERK [i.e., p70S6-kinase phosphorylated at Thr421/Ser424]).
Similar data were obtained, irrespective of the presence or absence of palmitate in the buffer. Moreover, the infarct-sparing effect of PostC was blocked by the ERK inhibitor PD98059 (infarct size: 68±7% vs 63±4% in PD-treated PostC vs control groups), consistent with a requisite role of ERK signaling in PostC-induced protection. In contrast, in the type-2 diabetic model, PostC did not activate ERK signaling and exacerbated (rather than reduced) infarct size (57±3%, 61±3% and 74±4%* in control, 3- and 6-cycle PostC groups; *p<.05 vs control) – outcomes that were not mitigated by addition of palmitate to the buffer. Similar loss of PostC-induced protection was seen with type-1 diabetes. Thus, PostC fails to reduce infarct size in the setting of both type-2 and type-1 diabetes, possibly due to impaired up-regulation of ERK signaling.