Enhanced pyruvate dehydrogenase activity improves cardiac outcomes in a murine model of cardiac arrest.
Enhanced pyruvate dehydrogenase activity improves cardiac outcomes in a murine model of cardiac arrest.
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DOI：
10.1371/journal.pone.0185046
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Sharp WW
中科院分区：
文献类型：
--
作者：
Piao L;Fang YH;Kubler MM;Donnino MW;Sharp WW
缺血后细胞代谢的变化改变了心肌和神经功能。丙酮酸脱氢酶（PDH）是线粒体葡萄糖氧化的限制性步骤，在缺血/再灌注损伤过程中，PDH激酶（PDK）表达增加可抑制PDH。这导致葡萄糖产生细胞ATP的利用率降低。心脏骤停（CA）后低温可改善预后并改变代谢，但其对CA后PDH和PDK活性的影响尚不清楚。我们假设CA后的治疗性低温（TH）与PDK活性的抑制和PDH活性的增加有关。我们进一步假设PDK活性抑制剂二氯醋酸盐（DCA）可改善PDH活性和CA后结局。麻醉和通气的成年雌性C57 BL/6野生型小鼠经历了12分钟KCl诱导的CA，随后进行心肺复苏。与常温（37°C）CA对照相比，给予TH（30°C）改善了总体生存率。（72小时存活率：62.5% vs. 28.6%，P<0.001），复苏后心肌功能（射血分数：50.9±3.1% vs. 27.2± 2.0%，P<0.001;主动脉收缩压：132.7±7.3 vs. 72.3±3.0 mmHg，P<0.001），CA后72小时神经功能评分（9.5±1.3 vs. 5.4±1.3，P<0.05）。在心脏和大脑中，CA增加乳酸浓度（分别增加1.9倍和3.1倍，P<0.01），降低PDH酶活性（分别减少24%和50%，P<0.01），并增加PDK蛋白表达（分别增加1.2倍和1.9倍，P<0.01）。相比之下，CA后用TH治疗使心脏和脑中的乳酸浓度（P<0.01和P<0.05）和PDK表达（P<0.001和P<0.05）恢复正常，同时增加PDH活性（P<0.01和P<0.01）。此外，在CA前30分钟给予DCA（0.2 mg/g体重）可改善常温动物CA后2小时的心肌血流动力学（主动脉收缩压：123±3 vs. 96±4 mmHg，P<0.001）和72小时存活率（50% vs. 19%，P<0.05）。TH或DCA给药时PDH活性增强与CA复苏后结局改善相关。PDH是改善CA后结局的有前景的治疗靶点。
Post-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. Anesthetized 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%, P<0.001), post-resuscitation myocardial function (ejection fraction: 50.9±3.1% vs. 27.2±2.0%, P<0.001; aorta systolic pressure: 132.7±7.3 vs. 72.3±3.0 mmHg, P<0.001), and neurological scores at 72-hour post CA (9.5±1.3 vs. 5.4±1.3, P<0.05). In both heart and brain, CA increased lactate concentrations (1.9-fold and 3.1-fold increase, respectively, P<0.01), decreased PDH enzyme activity (24% and 50% reduction, respectively, P<0.01), and increased PDK protein expressions (1.2-fold and 1.9-fold, respectively, P<0.01). In contrast, post-CA treatment with TH normalized lactate concentrations (P<0.01 and P<0.05) and PDK expressions (P<0.001 and P<0.05), while increasing PDH activity (P<0.01 and P<0.01) in both the heart and brain. Additionally, treatment with DCA (0.2 mg/g body weight) 30 min prior to CA improved both myocardial hemodynamics 2 hours post-CA (aortic systolic pressure: 123±3 vs. 96±4 mmHg, P<0.001) and 72-hour survival rates (50% vs. 19%, P<0.05) in normothermic animals. Enhanced 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.
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DOI：
10.1016/b978-0-12-394309-5.00006-7
发表时间：
2012
影响因子：
--
作者：
Kalogeris, Theodore;Baines, Christopher P.;Krenz, Maike;Korthuis, Ronald J.
通讯作者：
Korthuis, Ronald J.
影响因子：
15.1
作者：
Makino, J;Uchino, S;Bellomo, R
通讯作者：
Bellomo, R
DOI：
10.1152/ajpheart.2000.278.4.h1345
发表时间：
2000-04-01
影响因子：
4.8
作者：
Korvald, C;Elvenes, OP;Myrmel, T
通讯作者：
Myrmel, T
影响因子：
4.7
作者：
Piao, Lin;Marsboom, Glenn;Archer, Stephen L.
通讯作者：
Archer, Stephen L.
DOI：
10.1152/ajpheart.00404.2015
发表时间：
2015-11-01
影响因子：
4.8
作者：
Azam, Mohammed Ali;Wagg, Cory S.;Nanthakumar, Kumaraswamy
通讯作者：
Nanthakumar, Kumaraswamy