Abstract 843: Cardiomyocyte Overexpression of the Hydrogen Sulfide Producing Enzyme Cystathioine gamma-Lyase Attenuates Myocardial Ischemia-Reperfusion Injury
Background: Hydrogen sulfide (H2S) was recently discovered to be an endogenously produced gaseous second messenger capable of modulating many physiological processes. We have previously demonstrated that administration of a H2S donor limits the extent of myocardial infarction. This prompted us to investigate the potential of endogenously generated H2S in acute cardioprotection utilizing mice with transgenic overexpression of an H2S producing enzyme.
Methods: Mice with cardiac-specific overexpression of murine cystathionine γ-lyase (αMHC-CGL-Tg) were generated and analyzed for increased enzyme expression and H2S production utilizing a H2S specific polarographic electrode. αMHC-CGL-Tg and WT mice were then subjected to 45 min of in vivo LCA ischemia and 72 hr reperfusion and infarct size was evaluated using TTC staining.
Results: αMHC-CGL-Tg mice displayed an increased level of myocardial CGL RNA, which translated into a (15 fold) increase in protein expression. This increase in CGL enzyme resulted in a significant (2 fold) increase in H2S production by myocardial homogenates of αMHC-CGL-Tg mice. αMHC-CGL-Tg mice were found to have a 47% reduction in infarct size per area-at-risk (INF/AAR) as compared to WT littermates. AAR was similar between both groups.
Conclusions: This is the first evidence that overexpression of a H2S producing enzyme can decrease infarct size following MI-R injury. These findings demonstrate that modulation of endogenous H2S production may be of clinical benefit in ischemic disorders and that H2S generating enzymes may be viable therapeutic targets.