Extracellular CIRP aggravates cardiac dysfunction via the TLR4/MD2-NLRP3 axis during venoarterial ECMO.

OBJECTIVES

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiogenic shock (CS) inevitably induces systemic ischemia-reperfusion injury, which is accompanied by elevated levels of extracellular cold-inducible RNA-binding protein (CIRP) and an aggravated inflammatory response. However, the specific role of CIRP during VA-ECMO support remains unclear.

METHODS

CS patients undergoing VA-ECMO were enrolled, and serum CIRP expression levels were measured. A myocardial infarction-induced CS rat model with VA-ECMO was established. Myocardial tissue and serum were analyzed by ELISA, immunohistochemistry, and Western blotting. Cardiac function was assessed via echocardiography. CIRP-knockout rats and the CIRP antagonist C23 were used to investigate CIRP's role, and H9c2 cells were utilized to investigate the effects of recombinant CIRP in vitro.

RESULTS

In VA-ECMO patients, serum CIRP levels were significantly higher in non- survivors compared to survivors. Similarly, in the VA-ECMO-assisted CS rat model,rats with high CIRP expression exhibited greater myocardial injury. Administration of exogenous CIRP significantly exacerbated myocardial injury during VA-ECMO. In contrast, genetic deletion of CIRP attenuated both myocardial injury and inflammation during VA-ECMO. Furthermore, CIRP was associated with activation of the NLRP3 inflammasome and aggravated cardiomyocyte injury. In vivo, treatment with the C23 significantly alleviated myocardial injury and inflammation under VA-ECMO.

CONCLUSIONS

In patients with CS supported by VA-ECMO, elevated serum CIRP levels were significantly associated with poor survival outcomes. CIRP aggravated myocardial injury and inflammation, accompanied by NLRP3 activation.Pharmacological inhibition of CIRP mitigated myocardial damage during VA-ECMO, suggesting its potential as a therapeutic target for attenuating cardiac injury in CS patients.