Abstract Wed016: Loss of β 2 Adrenergic Receptor S-nitrosylation Protects Against Myocardial Injury

Background: Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Signaling through G protein-coupled receptors (GPCRs), such β adrenergic receptors (βARs), plays a critical role in heart function and pathology. Under pathogenic conditions, myocardial βAR dysfunction contributes to pathogenesis progression by excessive signal uncoupling and receptor desensitization, leading to myocyte death and contractility defects. It has been shown that the activation of β 2 ARs mediates myocyte survival and can exert cardioprotective effects against I/R injury. Moreover, it has been reported that β 2 AR S-nitrosylation at Cys265 drives receptor desensitization and caveolar internalization, whereas β 2 AR, lacking the S-nitrosylation site, exhibits prolonged signaling. Therefore, we aimed to investigate the role of SNO-β 2 AR in cardiac signaling and acute myocardial dysfunction after I/R injury. Methods: Female and male wild-type (WT) C57BL/6 mice and transgenic mice lacking the β 2 AR S-nitrosylation site (β 2 AR-C265S knock-in (KI) mice) were submitted to myocardium injury by coronary artery ligation. Myocardial injury was induced with 60 min of ischemia, followed by 24 h of reperfusion. Mice were submitted to increasing doses of isoproterenol (ISO) (0.5, 1, 5 and 10 ng) to determine hemodynamic parameters . In vivo experiments, molecular and biochemistry assays were performed 24 h after I/R surgery. Results: Our results show that: i) β 2 AR-C265S KI responses to ISO were increased when compared to β 2 AR WT; ii) I/R-induced infarct size was reduced in β 2 AR-C265S KI (32%) compared to β 2 AR WT (57%), whereas infarct area at risk did not change amoung the groups; iii) Ejection fraction (EF), left ventricular (LV) mass and Fractional shortening (FS) was improved in β 2 AR-C265S KI mice 24 h after I/R surgery. Conclusions: Our data show that mice with β 2 AR lacking the S-nitrosylation site exhibit prolonged receptor response. Moreover, β 2 AR-C265 KI mice displayed attenuated infarct size in a mouse model of acute myocardial I/R injury. The preservation of β 2 AR density and/or functionality in the heart may help to explain the cardioprotection observed in β 2 AR-C265S KI mice. Thus, S-nitrosylation is a central mechanism in β 2 AR signaling and may contribute to novel therapeutic interventions to promote cardioprotective signaling, shedding new light on pathogenesis and mechanisms of cardiac injury/repair with translational potential.