| Summary: | Using an experimental model of surgical deep hypothermic circulatory arrest (DHCA), we hypothesized that hibernating arctic ground squirrels (AGS) display reduced myocardial injury following I/R compared to a non-hibernator (rat) through reduced NF-kB signaling and myocardial inflammation. We further explored the role of myocardial accumulation of ceramides, known regulators of NF-kB inflammatory signaling, in the hibernator cardioprotective phenotype. Methods: Euthermic AGS aroused from torpor and rats underwent DHCA (45min, with 3 or 24h reperfusion) or sham. We compared between species/time points by two-way ANOVA: 1) biochemical severity of myocardial injury (plasma HFABP, TnI, ELISA); 2) myocardial apoptosis (activated caspase-3, immunostaining; TUNEL); 3) myocardial NF-kB activation (transcription factor binding assay; nuclear translocation) 4) myocardial cytokine expression and leukocyte extravasation; 5) myocardial PPARa activity (ELISA); 6) myocardial levels of 12 ceramides (MS) Results: Compared to rats, AGS displayed robust ischemic tolerance following DHCA (Fig A). This was accompanied by reduced NF-kB DNA binding activity and nuclear translocation (Fig B), as well as decreased expression of downstream inflammatory cytokines. Significant post-I/R accumulation of 4 species of sphingoid base ceramides and 1 monohexosyl ceramide was found in rat vs AGS. Preservation of myocardial PPARa activity occurred in AGS, but was significantly downregulated in the rat (Fig B). Conclusion: We found an association between the hibernator cardioprotective phenotype and differences in myocardial activation of NF-kB inflammatory signaling. Mechanistically, this was associated with a) accumulation of several species of ceramides in rat vs AGS hearts, previously implicated in triggering mitochondrial dysfunction and apoptosis following I/R; and b) preservation of PPARa activity in AGS, with known dual metabolic anti-inflammatory effects.
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