Peptidylarginine Deiminase 2 Knockout Improves Survival in Hemorrhagic Shock

BACKGROUND: The peptidylarginine deiminase (PAD) family converts arginine into citrulline through protein citrullination. PAD2 and PAD4 inhibitors can improve survival in hemorrhagic shock (HS). However, the impact of isoform specific PAD inhibition in improving survival has not been studied. In this study, we utilize selective Pad2 knockout (KO) mice to elucidate loss of function of PAD2 leads to pro-survival effect in HS. METHODS: HS: Pad2 and wild type (WT) mice (n = 5/group) were subjected to lethal HS (55% volume hemorrhage). Survival was monitored over seven days. Myocardial infarction (MI): Pad2 and WT mice (n = 9/group) were subjected to MI by permanent LAD ligation to examine the effect of ischemia on the heart. After 24 hours cardiac function and infarct size were measured. RESULTS: HS: Pad2 mice demonstrated 100% survival compared to 0% for WT mice (p = 0.002). In a sub-lethal HS model, cardiac β-catenin levels were higher in Pad2 compared to WT after 24 hours. MI: WT mice demonstrated larger MI (75%) compared to Pad2 (60%) (p < 0.05). Pad2 had significantly higher ejection fraction and fractional shortening compared to WT (p < 0.05). CONCLUSIONS: Pad2 improves survival in lethal HS. Possible mechanisms by which loss of PAD2 function improve survival include the activation of cell survival pathways, improved tolerance of cardiac ischemia and improved cardiac function during ischemia. PAD2 is promising as a future therapeutic target for the treatment of HS and cardiac ischemia.