title: Myocardial cytochrome oxidase activity is decreased following carbon monoxide exposure.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, PA, USA.
authors.forename: Kelechi N
authors.initials: KN
authors.lastname: Iheagwara
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Thom
authors.forename: Clifford S
authors.initials: CS
authors.lastname: Deutschman
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Levy
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000633:toxicity*; D002263:Carboxyhemoglobin / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006418:Heme / Q000031:analogs & derivatives / Q000378:metabolism; D000860:Hypoxia / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C027728:heme a; D006418:Heme; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D003576:Electron Transport Complex IV