Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA.
Cells. 2020 Jun 3;9(6):1393. doi: 10.3390/cells9061393.
Severe burn injury initiates a feedback cycle of inflammation, fibrosis, oxidative stress and cardiac mitochondrial damage via the PDE5A-cGMP-PKG pathway. To test if the PDE5A-cGMP-PKG pathway may contribute to burn-induced heart dysfunction. Sprague-Dawley rats were divided four groups: sham; sham/sildenafil; 24 h post burn (60% total body surface area scald burn, harvested at 24 h post burn); and 24 h post burn/sildenafil. We monitored heart function and oxidative adducts, as well as cardiac inflammatory, cardiac fibrosis and cardiac remodeling responses in vivo. Sildenafil inhibited the burn-induced PDE5A mRNA level and increased the cGMP level and PKG activity, leading to the normalization of PKG down-regulated genes (IRAG, PLB, RGS2, RhoA and MYTP), a decreased ROS level (HO), decreased oxidatively modified adducts (malonyldialdehyde [MDA], carbonyls), attenuated fibrogenesis as well as fibrosis gene expression (ANP, BNP, COL1A2, COL3A2, αSMA and αsk-Actin), and reduced inflammation and related gene expression (RELA, IL-18 and TGF-β) after the burn. Additionally, sildenafil treatment preserved left ventricular heart function (CO, EF, SV, LVvol at systolic, LVPW at diastolic and FS) and recovered the oxidant/antioxidant balance (total antioxidant, total SOD activity and Cu,ZnSOD activity). The PDE5A-cGMP-PKG pathway mediates burn-induced heart dysfunction. Sildenafil treatment recovers burn-induced cardiac dysfunction.
严重烧伤通过 PDE5A-cGMP-PKG 途径引发炎症、纤维化、氧化应激和心脏线粒体损伤的反馈循环。为了测试 PDE5A-cGMP-PKG 途径是否可能导致烧伤引起的心脏功能障碍。将 Sprague-Dawley 大鼠分为四组：假手术；假手术/西地那非；24 小时后烧伤（60%全身表面积烫伤烧伤，在烧伤后 24 小时收获）；和 24 小时后烧伤/西地那非。我们监测了心脏功能和氧化加合物，以及体内的心脏炎症、心脏纤维化和心脏重塑反应。西地那非抑制烧伤诱导的 PDE5A mRNA 水平，并增加 cGMP 水平和 PKG 活性，导致 PKG 下调基因（IRAG、PLB、RGS2、RhoA 和 MYTP）正常化，ROS 水平（HO）降低，氧化修饰加合物（丙二醛 [MDA]、羰基）减少，纤维化减少，纤维化基因表达（ANP、BNP、COL1A2、COL3A2、αSMA 和 αsk-Actin）减弱，炎症和相关基因表达（RELA、IL-18 和 TGF-β）减弱。此外，西地那非治疗可维持左心室心脏功能（CO、EF、SV、LVvol 在收缩期、LVPW 在舒张期和 FS），并恢复氧化应激/抗氧化平衡（总抗氧化剂、总 SOD 活性和 Cu，ZnSOD 活性）。PDE5A-cGMP-PKG 途径介导烧伤引起的心脏功能障碍。西地那非治疗可恢复烧伤引起的心脏功能障碍。
