Apelin-13 Attenuates Lipopolysaccharide-Induced Inflammatory Responses and Acute Lung Injury by Regulating PFKFB3-Driven Glycolysis Induced by NOX4-Dependent ROS

Abstract

Purpose Acute lung injury (ALI) is a life-threatening condition with limited therapeutic options. Macrophage inflammation plays a key role in the development of ALI. Abnormal glycolysis of macrophages contributes to the inflammatory response. However, the role of macrophage glycolysis in ALI still requires investigation. Apelin-13 has been shown to protect against ALI, whereas the underlying mechanisms remain unclear. In this study, we explored the effect of apelin-13 on lipopolysaccharide (LPS)-induced inflammation and ALI via regulation of glycolysis by modulating redox homeostasis in macrophages. Methods Serums from 34 patients with sepsis and 13 healthy volunteers were analyzed. In vivo, the protective effect of apelin-13 against LPS-induced ALI was evaluated using a mouse model of LPS-induced ALI. In vitro, mouse bone marrow macrophages (BMDMs) were pretreated with the antioxidant, NADPH oxidase (NOX) 4 (NOX4) small-interfering RNA (siRNA), the 6-phosphofructo-2 -kinase/fructose- 2,6-biphosphatase 3 (PFKFB3) siRNA, or the PFKFB3 overexpression plasmid before exposure to LPS. Results Serum apelin-13 levels were significantly elevated in patients with sepsis and sepsis-associated acute respiratory distress syndrome (ARDS) ( P <0.0001). In vivo, apelin-13 suppressed LPS-induced ALI and inflammatory cytokine production ( P <0.05). Furthermore, apelin-13 reduced hydrogen peroxide (H 2 O 2 ) content, NOX4 protein levels, and glycolysis. In vitro, LPS stimulation elevated NOX4 protein levels and reactive oxygen species (ROS) production ( P <0.05). These changes resulted in the accumulation of glycolysis in BMDMs. Treatment with antioxidant or NOX4 siRNA inhibited LPS-induced glycolysis and inflammatory cytokine production ( P <0.05). Moreover, in vitro experiments revealed that PFKFB3 regulates the release of pro-inflammatory cytokines by modulating glycolysis. In contrast, the action of apelin-13 opposed the effects of LPS. Conclusion In conclusion, apelin-13 protects against LPS-induced inflammatory responses and ALI by regulating PFKFB3-driven glycolysis induced by NOX4-dependent ROS.

Extracellular vesicles derived from CD4+ T cells carry DGKK to promote sepsis-induced lung injury by regulating oxidative stress and inflammation

“…The inhibition of PKC or NOX4 attenuated Pseudomonas aeruginosa -induced lung inflammatory injury by inhibiting ROS production [ 40 ] and LPS-induced ALI by inhibiting apoptosis and secretion of proinflammatory cytokines in pneumonia cells [ 41 ]. Serum apelin-13 could protect against sepsis-induced ALI by regulating NOX4-dependent ROS [ 42 ]. NOX4 (versus other NOX isoforms) was specifically involved in damage of the endothelial cell barrier in the lungs of a mouse model of CLP-induced sepsis [ 43 ].…”

Effect and mechanism of apelin on lipopolysaccharide induced acute pulmonary vascular endothelial barrier dysfunction

“…APJ is the endogenous receptor of apelin, and apelin-13 is the most active ligand of APJ 22 . In LPS-induced ALI, apelin can effectively improve the inflammatory response of lung tissue and reduce mortality in mice 23 . However, the exact molecular mechanism by which apelin acts is not yet clear.…”

Identification and Validation of Lactate Metabolism-Related Genes in Retinopathy of Prematurity

“…Apelin, a group of small peptides, is an endogenous ligand for angiotensin type 1 receptor associated protein. Yuan et al have demonstrated that apelin-13 can regulate ROS and inhibit glycolysis of macrophages, thereby reducing the release of in ammatory cytokine and improve acute lung injury 24 . Our GSEA analysis also further corroborated the above results.…”