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 isoformspecific PAD inhibition in improving survival has not been studied. In this study, we utilize selective Pad2(-/-) knockout 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 7 days. Myocardial infarction (MI): Pad2(-/-) and WTmice (n = 9/group) were subjected to MI by permanent LAD ligation to examine the effect of ischemia on the heart. After 24 h cardiac function and infarct size were measured. Results: HS: Pad2(-/-) mice demonstrated 100% survival compared with 0% forWTmice ( P = 0.002). In a sub-lethal HS model, cardiac beta-catenin levelswere higher in Pad2(-/-) compared with WT after 24 h. MI: WT mice demonstrated larger MI (75%) compared with Pad2(-/-) (60%) (P < 0.05). Pad2(-/-) had significantly higher ejection fraction and fractional shortening compared with WT (P< 0.05). Conclusions: Pad2(-/-) improves survival in lethal HS. Possible mechanisms by which loss of PAD2 function improves 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.