Abstract 18362: Proteomic and Metabolomic Profiling After Ischemia-Reperfusion Injury Reveals Bottlenecks That Underlie Cardioprotection in Hibernating Mammals

Abstract

Introduction: Mammalian hibernation is a natural molecular adaptation to extreme environmental conditions with important applications for perioperative organ protection. We have previously shown in a surgical model of deep hypothermic circulatory arrest (DHCA) robust cardioprotection in hibernating arctic ground squirrels (AGS) compared with Brown Norway rats (Figure). We conducted an integrated proteomic and metabolomic analysis to identify species and season-specific correlates of the cardioprotective phenotype. Methods: Quantitative 5-fraction 2D-LC/LC-MS/MS was used to identify proteins expressed in the myocardium of summer active AGS, winter hibernating AGS, and rats subjected to DHCA followed by 3h or 24h of reperfusion, or sham (n=3-5/group). The complete sets of 5250 peptides for AGS and 8482 peptides for Rat were matched using an ENSEMBL referenced orthology map. Peptides from the same matched protein and species were log-transformed and summarized into protein level profiles by means of principal component analysis. Myocardial levels of 167 metabolites were quantified by MS. Results: Differentially expressed metabolic enzymes or transporters are paired with substrate and product in Table and reported as a ratio of change over baseline by species and hibernation status. Compared to AGS, rats developed metabolic TCA cycle substrate flux bottlenecks at the level of succinate dehydrogenase and malate transporter. Conclusions: Integration of observed changes in protein abundance with metabolic modules identified specific druggable targets for metabolic optimization that underlie the hibernator cardioprotective phenotype.