LAUSR

Severe burn injury initiates a feedback cycle of inflammation, fibrosis and oxidative stress and others that may contribute to heart dysfunction via the PDE5A-cGMP-PKG pathway. Sildenafil (SIL) has been shown decrease immune adverse events in multiple cardiac diseases by inhibition of PDE5A. In this study, using Nano LC MS/MS strategy to identify differentially expressed proteins, we will determined the pathological importance of PDE5A-dependent injury in burn-related heart dysfunction using our well-established rat model with 4 groups: sham; sham/SIL (sham with sildenafil injection); 24 hpb (60% total body surface area scald burn and harvested at 24 hours post burn) and 24 hpb/SIL (24 hpb with SIL immediately after burn). We performed proteomics, Vevo 2100 ECG, qPCR, histology and ELISA to test our hypothesis. Our results show Sildenafil 1) inhibited burn-induced PDE5A mRNA, 2) increased cGMP and PKG activity leading to recover of PKG down-regulated genes (IRAG, PLB, RGS2, RhoA and MYTP), 3) decreased the ROS level (H2O2), oxidatively modified adducts (malonyldialdehyde (MDA), carbonyls), fibrotic gene expression (ANP, BNP, COL1A2, COL3A2, aSMA and αsk-Actin), inflammation-related gene expression (RELA, IL-18 and TGF-β) from burned rats (BRs) and 4) preserved Left-ventricular heart function (CO, EF, SV, LVvol at systolic, LVPW at diastolic and FS) and restored the oxidant/antioxidant balance (total antioxidant, total SOD activity and Cu,ZnSOD activity) in BRs. We demonstrate that the PDE5A-cGMP-PKG pathway mediates burn-induced heart dysfunction and will provide the theoretic foundation to guide pre-clinical translational study of Sildenafil in burned patients.