Abstract PR467

Abstract

Background & Objectives: Isoflurane postconditioning (IsoPostC) against myocardial ischemia reperfusion injury (IRI) is significantly decreased in diabetes. The underlying mechanism is unclear. Signal transducer and activator of transcription 3 (STAT3) is critical in ischemic postconditioning cardioprotection which is reduced in diabetic hearts as well as decreased expressions of cardiac Brahma-related gene 1 (Brg1) and nuclear factor-erythroid 2-related factor 2 (Nrf2). We hypothesized that Brg1/Nrf2 and STAT3 activation may play a critical role in IsoPostC-mediated cardioprotection in normal and diabetic hearts. Materials & Methods: Non-diabetic (C) and 8-week streptozotocin-induced type-1 diabetic (D) rat hearts were perfused ex vivo using Langendorff-perfused model. Rat hearts were subjected to 30 minutes global ischemia and 120 minutes of reperfusion with or without IsoPostC. IsoPostC was achieved by administrating emulsified isoflurane(2.0%, v/v) at the onset of reperfusion for 10 min. Left ventricular (LV) function was assessed throughout the experiment. Myocardial infarct size (IS) in relation to the area at risk (AAR) was used to measure the extent of myocardial injury. Cell injury was assessed by quantification of lactate dehydrogenase (LDH). Cardiac Nrf2, STAT3 and Brg1 protein expressions were measured using western blot. Results: (1)IsoPostC reduced myocardial IS in normal but not diabetic rats. (2) IsoPostC attenuated myocardial dysfunction in normal but not diabetic rats. (3) Brg1, Nrf2 and STAT3 protein expressions were enhanced in normal but decreased in diabetic rats. (4) The beneficial effects of IsoPostC were abolished by Brg1, Nrf2 or STAT3 gene knockdown.Conclusion: Our results indicate that IsoPostC confers cardioprotection through Brg1/Nrf2/STAT3 signaling, and impairment of this pathway may be responsible for the loss of sensitivity to IsoPostC cardioprotectio in type 1 diabetes.