Abstract 3672: Seasonal Variation in Ischemia Tolerance in a True Mammalian Hibernator
True mammalian hibernation is a unique strategy for surviving extreme environmental stress during winter months. The molecular mechanisms of cardioprotection in hibernating models are not known, and furthermore, whether or not these mechanisms are innate to the myocardium or are switched on only in winter. We tested the hypothesis that a true mammalian hibernating species, the North American woodchuck (Marmota monax), might reveal mechanistic insight into ischemic preconditioning (IPC), during the winter when they are prepared to hibernate, but not in summer. Accordingly, woodchucks were studied in summer (n=5) and in winter (n=5). After surgical implantation of instrumentation to measure aortic, left atrial and left ventricular (LV) pressures, myocardial infarction was induced by 1 hr ligation of a proximal branch of the left anterior descending coronary artery (CA) followed by 2 hrs reperfusion. Body temperature, arterial blood gases, hemodynamics and tissue blood flows (radioactive microspheres) were similar between groups, at baseline and during CA occlusion (O). The ischemic area at risk (AAR), determined by alcian blue dye, was similar between groups (31±6 vs 30±3% of LV and septum). Myocardial infarction (measured using TTC and expressed as a fraction of the AAR) was 49±5.4% in summer woodchucks, and significantly less (p<0.01) in winter woodchucks, 11±3.2%. To determine if the protection was similar to either first or second window IPC, we examined the key proteins, via immunoblotting, mediating first window IPC, e.g., PKCepsilon (PKCe), phosphatidylinositol 3 kinase (PI3K), and second window IPC, e.g., inducible nitric oxide synthase (iNOS). In winter woodchucks, neither PKCe translocation, nor iNOS upregulation was observed, yet, we found increases in endothelial nitric oxide synthase (eNOS) and PI3K. An additional 4 woodchucks in winter underwent NOS inhibition, via administration of N-omega-nitro-L-arginine (L-NNA), resulting in a loss of cardioprotection demonstrated by an infarct size/AAR of 41±4%, similar to that in the summer woodchucks. Thus, the woodchuck heart in winter exhibits a novel form of IPC, which does not require an ischemic stimulus, and does not share all of the mechanisms of either first or second window IPC.