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.

Low-dose carbon monoxide treatment attenuates early pulmonary neutrophil recruitment after acid aspiration

“…The amount of carboxyhemoglobin in blood is dependent on the concentration of CO delivered and the exposure time (12). Studies have shown that concentrations up to 1,000 ppm are tolerated in humans (12) and mice (14). Concentrations of 3,000 ppm were lethal in a mouse model of CO-induced myocardial dysfunction (14), whereas another study suggested that a concentration of 10,000 ppm caused lethality (28).…”

“…Studies have shown that concentrations up to 1,000 ppm are tolerated in humans (12) and mice (14). Concentrations of 3,000 ppm were lethal in a mouse model of CO-induced myocardial dysfunction (14), whereas another study suggested that a concentration of 10,000 ppm caused lethality (28). The majority of pulmonary studies has demonstrated efficacy with 250 (4,7,22,28,29) or 500 (5, 10, 36) ppm of CO delivered by either mechanical ventilation or spontaneous inhalation (12).…”

Prenatal exposure to carbon monoxide delays postnatal cardiac maturation

“…28 Thus, alterations in metabolic pathways may be a further expression of delayed postnatal maturation. However, CO acts at several heme-proteins and cytochromes during acute exposure, 29 therefore it is also possible that these changes reflect adaptation to chronic impairment of myocardial cytochrome oxidase activity. Overall, their functional correlation remains speculative as an evaluation of metabolic features of cardiomyocytes from CO-exposed rats was not attempted at this stage.…”

Neurologic and Pregnancy Effects of Carbon Monoxide Exposure

“…In addition to COHb, the binding of CO to various cytochromes is also significant and is thought to be responsible for cytotoxicity. The marked decrease in cytochrome oxidase in experimental studies suggests a direct toxic effect [14]. Myocardial injury with ischemic ECG changes and elevated cardiac biomarkers were found in 37% of 230 patients with moderate to severe CO poisoning with 5% in-hospital mortality [11].…”