Cold-inducible RNA-binding protein as a novel target to alleviate blood-brain barrier damage induced by cardiopulmonary bypass

Hypothermia provides neuroprotection and alleviates cerebral injury after cardiopulmonary bypass (CPB). The mechanism of cold-inducible RNA-binding protein (CIRP), which has been reported to be facilitated by hypothermia and act as a critical regulatory protein in the brain, remains unclear in CPB. Hence, the role of CIRP on hypothermia CPB-induced brain injury was investigated in a rat model.

CIRP exerted important neuroprotective effects by alleviating BBB breakdown, which might be associated with transforming growth factor-β1-matrix metallopeptidase-9 signals in hypothermia CPB.

Cirp-/- rats were generated using the transcription activator-like effector nucleases-based genome editing technique. The animals were randomly allocated to 3 groups (n = 5, each group): sham group, CPB group, and CPB in Cirp-/- group (Cirp-/- group). Three biological replicates received RNA sequencing in the CPB and Cirp-/- groups. The relative protein expression of the hippocampus was detected. The integrity of the blood-brain barrier (BBB) was measured using transmission electron microscopy and immunoglobulin G immunostaining. Glial fibrillary acidic protein in serum was detected. The brain was fixed for histopathological assessment.

More differentially expressed genes of BBB leakage were clustered functionally by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Transforming growth factor-β1, matrix metallopeptidase-9, tumor necrosis factor-α, and malondialdehyde in the hippocampus were higher in the Cirp-/- group, whereas the interleukin-4 level was opposite. Furthermore, more serious BBB disruption in the Cirp-/- group was shown using transmission electron microscopy and immunoglobulin G extravasation. Moreover, Cirp-/- showed enhanced tight junction protein degradation and histopathologic injury in the hippocampus (pathological score, surviving hippocampal neurons, and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine, 5'-triphosphate nick-end labeling-positive neurons). Therefore, CIRP significantly alleviated neurologic injury. Conclusions: CIRP exerted important neuroprotective effects by alleviating BBB breakdown, which might be associated with transforming growth factor-β1-matrix metallopeptidase-9 signals in hypothermia CPB.