Abstract 15618: S-nitrosoglutathione Reductase is Essential for Protecting Female Hearts From Ischemia-Reperfusion Injury

Pre-menopausal female hearts exhibit reduced susceptibility to ischemia-reperfusion (I/R) injury compared to males. Our recent study suggests that this protection results in part from enhanced endothelial nitric oxide synthase (eNOS) activation and increased protein S -nitrosylation (SNO), which is a nitric oxide-derived cysteine modification that increases with cardioprotective stimuli. Interestingly, we also found that S -nitrosoglutathione reductase (GSNOR) activity was increased in female hearts compared to males, which would tend to favor decreased SNO levels. Since higher SNO levels were observed in female hearts, we hypothesized that GSNOR protects female hearts from nitrosative stress by preventing the accumulation of protein SNO levels. We subjected male and female mouse hearts to I/R injury via Langendorff perfusion (20 min isc, 90 min rep). Control female hearts exhibited increased functional recovery and decreased infarct size vs. control males (% of preischemic function: male: 51.5±2.8%, female: 74.2±4.4%, % infarct: male: 39.7±3.5%, female: 25.0±1.0%; p -/- hearts, with males showing a reduction in infarct size vs. control (% infarct: 27.3±5.3%), and females showing an increase (% infarct: 40.8±7.7%). These striking findings point to GSNOR as an essential mediator of sex-dependent myocardial SNO signaling, and suggest that different therapeutic strategies may be required to combat ischemic heart disease in males and females.