Enhanced pyruvate dehydrogenase activity improves cardiac outcomes in a murine model of cardiac arrest

RationalePost-ischemic changes in cellular metabolism alter myocardial and neurological function. Pyruvate dehydrogenase (PDH), the limiting step in mitochondrial glucose oxidation, is inhibited by increased expression of PDH kinase (PDK) during ischemia/reperfusion injury. This results in decreased utilization of glucose to generate cellular ATP. Post-cardiac arrest (CA) hypothermia improves outcomes and alters metabolism, but its influence on PDH and PDK activity following CA are unknown. We hypothesized that therapeutic hypothermia (TH) following CA is associated with the inhibition of PDK activity and increased PDH activity. We further hypothesized that an inhibitor of PDK activity, dichloroacetate (DCA), would improve PDH activity and post-CA outcomes.Methods and resultsAnesthetized and ventilated adult female C57BL/6 wild-type mice underwent a 12-minute KCl-induced CA followed by cardiopulmonary resuscitation. Compared to normothermic (37°C) CA controls, administering TH (30°C) improved overall survival (72-hour survival rate: 62.5% vs. 28.6%, PPPPPPPPPPPPPPPConclusionsEnhanced PDH activity in the setting of TH or DCA administration is associated with improved post-CA resuscitation outcomes. PDH is a promising therapeutic target for improving post-CA outcomes.研究背景与依据：缺血后细胞代谢改变会损害心肌与神经功能。丙酮酸脱氢酶（Pyruvate dehydrogenase, PDH）是线粒体葡萄糖氧化的限速步骤，在缺血/再灌注损伤期间，丙酮酸脱氢酶激酶（PDH kinase, PDK）表达上调可抑制其活性，进而降低葡萄糖用于合成细胞三磷酸腺苷（Adenosine triphosphate, ATP）的利用率。心脏骤停（Cardiac arrest, CA）后亚低温治疗可改善预后并调节代谢，但该疗法对CA后PDH与PDK活性的影响尚不明确。我们提出假说：心脏骤停后给予治疗性亚低温（Therapeutic hypothermia, TH）可抑制PDK活性并提升PDH活性。我们进一步提出假说：PDK活性抑制剂二氯乙酸盐（Dichloroacetate, DCA）可增强PDH活性并改善心脏骤停后预后。 方法与结果：对经麻醉并接受机械通气的成年雌性C57BL/6野生型小鼠实施12分钟氯化钾（KCl）诱导的心脏骤停，随后进行心肺复苏。与常温（37℃）心脏骤停对照组相比，给予TH（30℃）可提升整体生存率（72小时生存率：62.5% vs 28.6%，原文此处存在冗余的P字符）。 结论：在TH或DCA干预的情况下，增强PDH活性与心脏骤停后复苏预后改善显著相关。PDH是改善心脏骤停后预后的极具潜力的治疗靶点。