CTRP3 as a new therapeutic option to minimize hypoxic injury in post-resuscitation syndrome (PRS)

Background 

Post-resuscitation syndrome (PRS) occurs after the restoration of spontaneous blood flow following cardiac arrest. It triggers an inflammatory cascade with the release of reactive oxygen species (ROS) and multiple proinflammatory cytokines. Ischaemia/reperfusion injury increases oxidative stress, damages the endothelium and leads to loss of vascular resistance and capillary leakage. A critical factor in the vascular response to hypoxia is vascular endothelial growth factor (VEGF), which plays a key role in vascular remodelling and endothelial repair. Recent studies have shown that the adipokine C1q/TNF-related protein-3 (CTRP3) has anti-inflammatory effects on endothelial cells. However, the effect of CTRP3 under hypoxic conditions is still poorly understood, making CTRP3 an interesting therapeutic target.

Material and methods

An in vitro hypoxia model was established using endothelial cells (MyEND) and monocytic cells (J774A.1). Cells were cultured under normoxic (21% O2) and hypoxic (0.5% O2) conditions. The mRNA and protein levels of cytokines and VEGF were quantified by real-time PCR and ELISA at different time points. In addition, CTRP3 was added before hypoxia to investigate a possible protective effect.

Results

Both real-time PCR and ELISA showed a significant upregulation of the pro-inflammatory cytokines interleukin-6 (IL-6, ~9-fold, P<0.05) and interleukin-1β (IL-1β, ~2-fold, P<0.05) as well as VEGF (~2-fold, P<0.001) in the hypoxic cell culture model, indicating endothelial damage under hypoxic stress. Pre-incubation with CTRP3 attenuated hypoxia-induced VEGF up-regulation (P<0.05) and returned VEGF levels to normoxic levels. In addition, CTRP3 modulated the expression of pro-inflammatory cytokines, suggesting anti-inflammatory effects and possible protection against endothelial and tissue damage.

Conclusion

This study highlights key mechanisms of inflammation and endothelial injury in the PRS following hypoxic exposure and highlights CTRP3 as a promising therapeutic target. Targeted downregulation of VEGF and modulation of proinflammatory cytokines by CTRP3 suggest that this adipokine may attenuate the deleterious effects of hypoxia. These findings provide a basis for the development of CTRP3-based approaches to reduce inflammation and vascular stress in PRS to improve clinical outcomes after resuscitation. Further studies are required to validate the molecular mechanisms and therapeutic potential of CTRP3.