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Carbon monoxide pollution aggravates ischemic heart failure through oxidative stress pathway.

ABSTRACT: Risk of hospital readmission and cardiac mortality increases with atmospheric pollution for patients with heart failure. The underlying mechanisms are unclear. Carbon monoxide (CO) a ubiquitous environmental pollutant could be involved. We explored the effect of daily exposure of CO relevant to urban pollution on post-myocardial infarcted animals. Rats with ischemic heart failure were exposed 4 weeks to daily peaks of CO mimicking urban exposure or to standard filtered air. CO exposure worsened cardiac contractile dysfunction evaluated by echocardiography and at the cardiomyocyte level. In line with clinical reports, the animals exposed to CO also exhibited a severe arrhythmogenic phenotype with numerous sustained ventricular tachycardias as monitored by surface telemetric electrocardiograms. CO did not affect cardiac ?-adrenergic responsiveness. Instead, mitochondrial dysfunction was exacerbated leading to additional oxidative stress and Ca²⁺ cycling alterations. This was reversed following acute antioxidant treatment of cardiomyocytes with N-acetylcysteine confirming involvement of CO-induced oxidative stress. Exposure to daily peaks of CO pollution aggravated cardiac dysfunction in rats with ischemic heart failure by specifically targeting mitochondria and generating ROS-dependent alterations. This pathway may contribute to the high sensibility and vulnerability of individuals with cardiac disease to environmental outdoor air quality.

SUBMITTER: Reboul C

PROVIDER: S-EPMC5206643 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Carbon monoxide pollution aggravates ischemic heart failure through oxidative stress pathway.

Reboul Cyril C Boissière Julien J André Lucas L Meyer Gregory G Bideaux Patrice P Fouret Gilles G Feillet-Coudray Christine C Obert Philippe P Lacampagne Alain A Thireau Jérôme J Cazorla Olivier O Richard Sylvain S

Scientific reports 20170103

Risk of hospital readmission and cardiac mortality increases with atmospheric pollution for patients with heart failure. The underlying mechanisms are unclear. Carbon monoxide (CO) a ubiquitous environmental pollutant could be involved. We explored the effect of daily exposure of CO relevant to urban pollution on post-myocardial infarcted animals. Rats with ischemic heart failure were exposed 4 weeks to daily peaks of CO mimicking urban exposure or to standard filtered air. CO exposure worsened ...[more]

PMID: 28045070

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Project description:Prolonged or excessive stimulation from inhaled toxins may cause oxidative stress and DNA damage that can lead to stress-induced senescence in epithelial cells, which can contribute to several airway diseases. Mounting evidence has shown carbon monoxide (CO) confers cytoprotective effects. We investigated the effects of CO on oxidative stress-induced senescence in human airway epithelium and elucidated the underlying molecular mechanisms. Here, CO pretreatment reduced H2O2-mediated increases in total reactive oxygen species (ROS) production and mitochondrial superoxide in a human bronchial epithelial cell line (BEAS-2B). H2O2 treatment triggered a premature senescence-like phenotype with enlarged and flattened cell morphology accompanied by increased SA-β-gal activity, cell cycle arrest in G0/G1, reduced cell viability, and increased transcription of senescence-associated secretory phenotype (SASP) genes. Additionally, exposure to H2O2 increased protein levels of cellular senescence markers (p53 and p21), reduced Sirtuin 3 (SIRT3) and manganese superoxide dismutase (MnSOD) levels, and increased p53 K382 acetylation. These H2O2-mediated effects were attenuated by pretreatment with a CO-containing solution. SIRT3 silencing induced mitochondrial superoxide production and triggered a senescence-like phenotype, whereas overexpression decreased mitochondrial superoxide production and alleviated the senescence-like phenotype. Air-liquid interface (ALI) culture of primary human bronchial cells, which becomes a fully differentiated pseudostratified mucociliary epithelium, was used as a model. We found that apical and basolateral exposure to H2O2 induced a vacuolated structure that impaired the integrity of ALI cultures, increased goblet cell numbers, decreased SCGB1A1+ club cell numbers, increased p21 protein levels, and increased SASP gene transcription, consistent with our observations in BEAS-2B cells. These effects were attenuated in the apical presence of a CO-containing solution. In summary, we revealed that CO has a pivotal role in epithelial senescence by regulating ROS production via the SIRT3/MnSOD/p53/p21 pathway. This may have important implications in the prevention and treatment of age-associated respiratory pathologies.

Project description:In conventional clinical toxicology practice, the blood level of carboxyhemoglobin is a biomarker of carbon monoxide (CO) poisoning but does not correspond to the complete clinical picture and the severity of the poisoning. Taking into account articles suggesting the relationship between oxidative stress parameters and CO poisoning, it seems reasonable to consider this topic more broadly, including experimental biochemical data (oxidative stress parameters) and patients poisoned with CO. This article aimed to critically assess oxidative-stress-related parameters as potential biomarkers to evaluate the severity of CO poisoning and their possible role in the decision to treat. The critically set parameters were antioxidative, including catalase, 2,2-diphenyl-1-picryl-hydrazyl, glutathione, thiol and carbonyl groups. Our preliminary studies involved patients (n = 82) admitted to the Toxicology Clinical Department of the University Hospital of Jagiellonian University Medical College (Kraków, Poland) during 2015-2020. The poisoning was diagnosed based on medical history, clinical symptoms, and carboxyhemoglobin blood level. Blood samples for carboxyhemoglobin and antioxidative parameters were collected immediately after admission to the emergency department. To evaluate the severity of the poisoning, the Pach scale was applied. The final analysis included a significant decrease in catalase activity and a reduction in glutathione level in all poisoned patients based on the severity of the Pach scale: I°-III° compared to the control group. It follows from the experimental data that the poisoned patients had a significant increase in level due to thiol groups and the 2,2-diphenyl-1-picryl-hydrazyl radical, with no significant differences according to the severity of poisoning. The catalase-to-glutathione and thiol-to-glutathione ratios showed the most important differences between the poisoned patients and the control group, with a significant increase in the poisoned group. The ratios did not differentiate the severity of the poisoning. The carbonyl level was highest in the control group compared to the poisoned group but was not statistically significant. Our critical assessment shows that using oxidative-stress-related parameters to evaluate the severity of CO poisoning, the outcome, and treatment options is challenging.

Project description:Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Here, we show that production of cardiomyocyte NADPH (nicotinamide adenine dinucleotide phosphate), a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with cardiac cell death, fibrosis, and cardiomyopathy. We report that the pentose phosphate pathway (PPP) and mitochondrial serine/glycine/folate metabolic signaling, two major NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced in the heart by pressure overload. We identify ATF4 (activating transcriptional factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these two pathways. Consistent with this, joint pathway analysis (JPA) of transcriptomic and metabolomic data reveals that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in cardiomyocytes in culture leads to a significant increase in NADPH-producing enzymes whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression in vitro strongly augments metabolic flux within these two pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of pressure overload and accelerates the development of heart failure, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Taken together, our findings reveal that ATF4 plays a critical role in cardiac homeostasis under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.

Project description:Commonly used anesthetics induce widespread neuronal degeneration in the developing mammalian brain via the oxidative-stress-associated mitochondrial apoptosis pathway. Dysregulation of cytochrome oxidase (CcOX), the terminal oxidase of the electron transport chain, can result in reactive oxygen species (ROS) formation. Isoflurane has previously been shown to activate this enzyme. Carbon monoxide (CO), as a modulator of CcOX, is of interest because infants and children are routinely exposed to CO during low-flow anesthesia. We have recently demonstrated that low concentrations of CO limit and prevent isoflurane-induced neurotoxicity in the forebrains of newborn mice in a dose-dependent manner. However, the effect of CO on CcOX in the context of anesthetic-induced oxidative stress is unknown. Seven-day-old male CD-1 mice underwent 1h exposure to 0 (air), 5, or 100ppm CO in air with or without isoflurane. Exposure to isoflurane or CO independently increased CcOX kinetic activity and increased ROS within forebrain mitochondria. However, exposure to CO combined with isoflurane paradoxically limited CcOX activation and oxidative stress. There were no changes seen in steady-state levels of CcOX I protein, indicating post-translational modification of CcOX as an etiology for changes in enzyme activity. CO exposure led to differential effects on CcOX subunit I tyrosine phosphorylation depending on concentration, while combined exposure to isoflurane with CO markedly increased the enzyme phosphorylation state. Phosphorylation of tyrosine 304 of CcOX subunit I has been shown to result in strong enzyme inhibition, and the relative reduction in CcOX kinetics following exposure to CO combined with isoflurane may have been due, in part, to such phosphorylation. Taken together, the data suggest that CO modulates CcOX in the developing brain during isoflurane exposure, thereby limiting oxidative stress. These CO-mediated effects could have implications for the development of low-flow anesthesia in infants and children to prevent anesthesia-induced oxidative stress.

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Carbon monoxide pollution aggravates ischemic heart failure through oxidative stress pathway.

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Carbon monoxide pollution aggravates ischemic heart failure through oxidative stress pathway.

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