PRG4 mitigates hemorrhagic shock-induced cardiac injury by inhibiting mitochondrial dysregulation, oxidative stress and NLRP3-mediated pyroptosis

Hemorrhagic shock (HS) is one of the main causes of morbidity and death in patients with trauma or major surgery. Cardiac dysfunction is a well-known complication of HS. PRG4, also known as lubricin, is a mucin-like glycoprotein that plays anti-inflammatory and anti-apoptotic roles in a variety of diseases. In this study, we aimed to explore the cardioprotective efficacy of PRG4 in HS-induced cardiac injury. Employing the HS model and RNA-seq, we found that PRG4 was increased in the myocardial tissue of rats after HS. In vivo studies suggested that HS led to abnormal hemodynamic parameters and increased cTnI levels, and PRG4 overexpression effectively reversed these changes. PRG4 also suppressed HS-induced mitochondrial disorders, as reflected by increased mitochondrial membrane potential (MMP), ATP and mitochondria cytochrome c , COXIV and TOM20, as well as decreased BNIP3L and cytoplasmic cytochrome c . Furthermore, HS led to enhanced oxidative stress, as evidenced by upregulated ROS and MDA contents, and downregulated SOD and CAT activities, and these alterations were negated by PRG4 overexpression. Notably, PRG4 repressed the NLRP3-mediated pyroptosis pathway, as illustrated by decreased NLRP3 levels, caspase-1 activity and GSDMD-NT levels. In summary, these observations indicate that PRG4 overexpression protects against HS-induced cardiac dysfunction by inhibiting mitochondrial dysregulation, oxidative stress and NLRP3-mediated pyroptosis.

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