Iheagwara Kelechi N, Thom Stephen R, Deutschman Clifford S, Levy Richard J
Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, PA, USA.
Biochim Biophys Acta. 2007 Sep;1772(9):1112-6. doi: 10.1016/j.bbadis.2007.06.002. Epub 2007 Jun 16.
Carbon monoxide (CO) inhalation often leads to cardiac dysfunction, dysrhythmias, ischemia, infarction, and death. However, the underlying mechanism of CO toxicity is poorly understood. We hypothesize that inhaled CO interrupts myocardial oxidative phosphorylation by decreasing the activity of myocardial cytochrome oxidase (CcOX), the terminal oxidase of the electron transport chain. Male C57Bl6 mice were exposed to either 1000 ppm (0.1%) CO or air for 3 h. Cardiac ventricles were harvested and mitochondria were isolated. CcOX kinetics and heme aa(3) content were measured. V(max), K(m), and turnover number were determined. Levels of CcOX subunit I message and protein were evaluated. Carboxyhemoglobin (COHb) levels were measured and tissue hypoxia was assessed with immunohistochemistry for pimonidazole hydrochloride. CO significantly decreased myocardial CcOX activity and V(max) without altering K(m). Heme aa(3) content and CcOX I protein levels significantly decreased following CO exposure while enzyme turnover number and CcOX I mRNA levels remained unchanged. CO exposure increased COHb levels without evidence of tissue hypoxia as compared to sham and hypoxic controls. Decreased CcOX activity following CO inhalation was likely due to decreased heme aa(3) and CcOX subunit I content. Importantly, myocardial CcOX impairment could underlie CO induced cardiac dysfunction.
吸入一氧化碳（CO）常导致心脏功能障碍、心律失常、缺血、梗死和死亡。然而，CO毒性的潜在机制尚不清楚。我们推测，吸入的CO通过降低心肌细胞色素氧化酶（CcOX）的活性来中断心肌氧化磷酸化，CcOX是电子传递链的末端氧化酶。将雄性C57Bl6小鼠暴露于1000 ppm（0.1%）的CO或空气中3小时。采集心脏心室并分离线粒体。测量CcOX动力学和血红素aa3含量。测定Vmax、Km和周转数。评估CcOX亚基I的信使核糖核酸和蛋白质水平。测量碳氧血红蛋白（COHb）水平，并用盐酸匹莫硝唑免疫组织化学评估组织缺氧情况。CO显著降低心肌CcOX活性和Vmax，而不改变Km。CO暴露后，血红素aa3含量和CcOX I蛋白水平显著降低，而酶周转数和CcOX I信使核糖核酸水平保持不变。与假手术组和缺氧对照组相比，CO暴露增加了COHb水平，但没有组织缺氧的证据。吸入CO后CcOX活性降低可能是由于血红素aa3和CcOX亚基I含量减少。重要的是，心肌CcOX损伤可能是CO诱导心脏功能障碍的基础。
