Merante F, Mickle D A, Weisel R D, Li R K, Tumiati L C, Rao V, Williams W G, Robinson B H
Centre for Cardiovascular Research, The Toronto Hospital and the University of Toronto, Toronto, Ontario, Canada M5G 2C4.
Am J Physiol. 1998 Nov;275(5):H1673-81. doi: 10.1152/ajpheart.1998.275.5.H1673.
A human pediatric cardiomyocyte cell culture model of chronic cyanosis was used to assess the effects of low oxygen tension on mitochondrial enzyme activity to address the postoperative increase in lactate and decreased ATP in the myocardium and the high incidence of low-output failure with restoration of normal oxygen tension, after technically successful corrective cardiac surgery. Chronically hypoxic cells (PO2 = 40 mmHg for 7 days) exhibited significantly reduced activities for pyruvate dehydrogenase, cytochrome-c oxidase, succinate cytochrome c reductase, succinate dehydrogenase, and citrate synthase. The activity of NADH-cytochrome c reductase was unaffected. Lactate production and the lactate-to-pyruvate ratio were significantly greater in hypoxic cardiomyocytes. Western and Northern analysis demonstrated a decrease in the levels of various mRNA and corresponding polypeptides in hypoxic cells. Thus hypoxia influences mitochondrial metabolism through acute and chronic adaptive mechanisms, reflecting allosteric (posttranscriptional) and transcriptional modulation. Transcriptional downregulation of key mitochondrial enzyme systems can explain the insufficient myocardial aerobic metabolism and low-output failure in children with cyanotic heart disease after cardiac surgery.
采用人类小儿慢性发绀心肌细胞培养模型，评估低氧张力对线粒体酶活性的影响，以解决在技术上成功进行心脏矫正手术后，心肌中乳酸增加、三磷酸腺苷（ATP）减少以及恢复正常氧张力后低心排血量衰竭发生率高的问题。长期缺氧的细胞（7天内氧分压为40 mmHg）丙酮酸脱氢酶、细胞色素c氧化酶、琥珀酸细胞色素c还原酶、琥珀酸脱氢酶和柠檬酸合酶的活性显著降低。NADH-细胞色素c还原酶的活性未受影响。缺氧心肌细胞中乳酸生成及乳酸与丙酮酸的比值显著更高。蛋白质免疫印迹法和Northern印迹法分析表明，缺氧细胞中各种信使核糖核酸（mRNA）和相应多肽水平降低。因此，缺氧通过急性和慢性适应性机制影响线粒体代谢，反映变构（转录后）和转录调节。关键线粒体酶系统的转录下调可解释心脏手术后患有青紫型心脏病儿童心肌有氧代谢不足和低心排血量衰竭的原因。
