Small Ubiquitin-Like Modifier 3 Attenuates Lung Ischemia-Reperfusion Injury Progression by Inhibiting Endoplasmic Reticulum Stress through Heat Shock Protein 70.

Dysfunction of SUMOylation is closely associated with various diseases, yet its role in lung ischemia-reperfusion injury (LIRI) remains poorly understood. This study used quantitative real-time PCR and Western blot to assess the expression levels of small ubiquitin-like modifier 3 (SUMO3) and heat shock protein 70 (HSP70). The stability of HSP70 and protein-protein interactions were also detected. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining were performed to detect cell apoptosis. Immunofluorescence was applied to assess the expression levels of Bip, phosphorylated protein kinase r-like endoplasmic reticulum kinase, and phosphorylated inositol-requiring enzyme 1. Enzyme-linked immunosorbent assay kits were used to measure the content of cytokines. This study found that SUMO3 was down-regulated in both the hypoxia/reoxygenation-induced cell model and the in vivo ischemia-reperfusion injury-mediated lung injury model. SUMO3 up-regulation effectively promoted cell growth in vitro and attenuated lung injury in vivo. Mechanistically, SUMO3 interacts with HSP70 and promotes its SUMOylation, thereby stabilizing HSP70 protein and subsequently suppressing endoplasmic reticulum (ER) stress. Knockdown of HSP70 reversed the beneficial effects induced by SUMO3 up-regulation, such as inhibiting cell growth and activating ER stress in vitro and aggravating lung injury and enhancing inflammatory response in vivo. These findings demonstrate that SUMO3 exerts a protective role in LIRI progression by stabilizing HSP70 and inhibiting ER stress, providing a potential therapeutic strategy for LIRI treatment.