Research ArticleCardiology

Chronic hypoxia–induced Cirbp hypermethylation attenuates hypothermic cardioprotection via down-regulation of ubiquinone biosynthesis

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Science Translational Medicine  24 Apr 2019:
Vol. 11, Issue 489, eaat8406
DOI: 10.1126/scitranslmed.aat8406

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  • RE: reply to the comment from Dr.Zhou

    Thanks for your constructive comments. I agree with you that chronic hypoxia-induced pulmonary hypertension (PAH) might reduce the cardioprotective effects of hypothermia, and act as a potential confounding factor in our study. However, it is no doubt that every pathological phenomenon involves lots of molecular processes, and the most important thing is to figure out its underlying key mechanism. In our study, we found that chronic hypoxia-induced Cirbp hypermethylation impaired cardiac CoQ10 biosynthesis during cardiopulmonary bypass. Most importantly, we found that overexpression of CIRBP or addition of COQ10 to cardioplegic solution could significantly improve the cardioprotective effect for chronically hypoxic myocardium, which illustrates that the hypoxia-CIRBP-COQ10 axis is a major contributor in our study, and could be a potential translational target in future. On the other hand, to conclude that depressed CIRBP expression was a result of chronic hypoxia instead of PAH, we used the cardiac tissues harvested from the left ventricle of rats and from the right atrial appendage of patients, because the influence of PAH on heart mainly presents with increased workload for the right ventricle. Moreover, the experimental results from the study of neonatal rat cardiac myocytes adds another layer of evidence to our finding, because these cells are exempt from the direct impact of in vivo pressure load. If you have any more questions, please let me know.

    Competing Interests: None declared.
  • RE:

    Liu and colleagues elegantly demonstrated the significance of CIRBP in cardioprotective effects of the therapeutic hypothermia and showed that chronic hypoxia-induced suppression of CIRBP is likely responsible for the high risk of severe myocardial injury after cardiac surgery. Interestingly, the authors exposed rats to 10% oxygen for four weeks to achieve hypoxia. As the authors rightly pointed out, hypoxia is a common stimulus to induce pulmonary hypertension, which leads to right ventricular hypertrophy and failure. Since cardiac surgery in patients with pulmonary hypertension is associated with high morbidity and mortality, it is possible that the reduced cardiac protection in their model of hypoxic rats is because that hypoxic rats are already hypertensive. Consistently, hypothermia is known to exacerbates pulmonary hypertension. Although authors showed that hypoxia suppressed CIRBP in cultured neonatal rat cardiac myocytes, they only analyzed cardiac tissues from the left ventricle of hypoxic rats and from the right atrial appendage tissues in patients with chronic hypoxia, making it difficult to conclusively distinguish the role of hypoxia from that of pulmonary hypertension in this study. Another interesting finding of the study is that CIRBP may exert its cardiac protection via maintaining the homeostasis of the ubiquinone synthesis, which is consistent with the conventional thoughts that hypothermia may provide cardioprotective effects via reducing tissues’ metab...

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    Competing Interests: None declared.