Chronic Hypoxia-Induced Cirbp Hypermethylation Attenuates Hypothermic Cardioprotection Via Down-Regulation Of Ubiquinone Biosynthesis

Therapeutic hypothermia is commonly used during cardiopulmonary bypass (CPB) to protect the heart against myocardial injury in cardiac surgery. Patients who suffer from chronic hypoxia (CH), such as those with certain heart or lung conditions, are at high risk of severe myocardial injury after cardiac surgery, but the underlying mechanisms are unknown. This study tested whether CH attenuates hypothermic cardioprotection during CPB. Using a rat model of CPB, we found that hypothermic cardioprotection was impaired in CH rats but was preserved in normoxic rats. Cardiac proteomes showed that cold-inducible RNA binding protein (CIRBP) was significantly (P = 0.03) decreased in CH rats during CPB. Methylation analysis of neonatal rat cardiomyocytes under CH and myocardium specimens from patients with CH showed that CH induced hypermethylation of the Cirbp promoter region, resulting in its depression and failure to respond to cold stress. Cirbp-knockout rats showed attenuated hypothermic cardioprotection, whereas Cirbp-transgenic rats showed an enhanced response. Proteomics analysis revealed that the cardiac ubiquinone biosynthesis pathway was down-regulated during CPB in Cirbp-knockout rats, resulting in a significantly (P = 0.01) decreased concentration of ubiquinone (CoQ10). Consequently, cardiac oxidative stress was aggravated and adenosine 5'-triphosphate production was impaired, leading to increased myocardial injury during CPB. CoQ10-supplemented cardioplegic solution improved cardioprotection in rats exposed to CH, but its effect was limited in normoxic rats. Our study suggests that an individualized cardioprotection strategy should be used to fully compensate for the consequences of epigenetic modification of Cirbp in patients with CH who require therapeutic hypothermia.