Mingyue Liu1, Yongnan Li2, Yiwei Liu1, Shujie Yan1, Gang Liu1, Qiaoni Zhang1, Bingyang Ji3. 1. Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. 2. Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China; Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China. 3. Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Electronic address: jibingyang@fuwai.com.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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.
BACKGROUND: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. METHODS: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. RESULTS: 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.
Authors: Mayuko Wakimoto; Joseph H Patrick; Yoshikazu Yamaguchi; Catherine Roth; Marco Corridore; Joseph D Tobias Journal: Saudi J Anaesth Date: 2022-03-17