title: Carbon monoxide increases inducible NOS expression that mediates CO-induced myocardial damage during ischemia-reperfusion.
abstract: We investigated the role of inducible nitric oxide (NO) synthase (iNOS) on ischemic myocardial damage in rats exposed to daily low nontoxic levels of carbon monoxide (CO). CO is a ubiquitous environmental pollutant that impacts on mortality and morbidity from cardiovascular diseases. We have previously shown that CO exposure aggravates myocardial ischemia-reperfusion (I/R) injury partly because of increased oxidative stress. Nevertheless, cellular mechanisms underlying cardiac CO toxicity remain hypothetical. Wistar rats were exposed to simulated urban CO pollution for 4 wk. First, the effects of CO exposure on NO production and NO synthase (NOS) expression were evaluated. Myocardial I/R was performed on isolated perfused hearts in the presence or absence of S-methyl-isothiourea (1 μM), a NOS inhibitor highly specific for iNOS. Finally, Ca(2+) handling was evaluated in isolated myocytes before and after an anoxia-reoxygenation performed with or without S-methyl-isothiourea or N-acetylcystein (20 μM), a nonspecific antioxidant. Our main results revealed that 1) CO exposure altered the pattern of NOS expression, which is characterized by increased neuronal NOS and iNOS expression; 2) cardiac NO production increased in CO rats because of its overexpression of iNOS; and 3) the use of a specific inhibitor of iNOS reduced myocardial hypersensitivity to I/R (infarct size, 29 vs. 51% of risk zone) in CO rat hearts. These last results are explained by the deleterious effects of NO and reactive oxygen species overproduction by iNOS on diastolic Ca(2+) overload and myofilaments Ca(2+) sensitivity. In conclusion, this study highlights the involvement of iNOS overexpression in the pathogenesis of simulated urban CO air pollution exposure.
authors.affiliation: Université d'Avignon, Avignon, France;
authors.forename: Grégory
authors.initials: G
authors.lastname: Meyer
authors.affiliation: Institut national de la santé et de la recherche médicale, Université Montpellier1, Université Montpellier2, Montpellier, France;
authors.forename: Lucas
authors.initials: L
authors.lastname: André
authors.affiliation: Université d'Avignon, Avignon, France;
authors.forename: Adrien
authors.initials: A
authors.lastname: Kleindienst
authors.affiliation: Fédération de Médecine Translationelle, Faculty of Medicine, Université de Strasbourg, Strasbourg France;
authors.forename: François
authors.initials: F
authors.lastname: Singh
authors.affiliation: Université d'Avignon, Avignon, France; Laboratoire Techniques for biomedical engineering and complexity management-informatics, mathematics, and applications-Grenoble, Bâtiment Jean Roget-Domaine de la Merci, Université Joseph Fourier, La Tronche Cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Tanguy
authors.affiliation: Institut national de la santé et de la recherche médicale, Université Montpellier1, Université Montpellier2, Montpellier, France;
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.affiliation: Université d'Avignon, Avignon, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Obert
authors.affiliation: Laboratoire Techniques for biomedical engineering and complexity management-informatics, mathematics, and applications-Grenoble, Bâtiment Jean Roget-Domaine de la Merci, Université Joseph Fourier, La Tronche Cedex, France.
authors.forename: François
authors.initials: F
authors.lastname: Boucher
authors.affiliation: Centre de Pharmacologie et Innovation dans le Diabète, Faculty of Pharmacy, Université Montpellier1, Montpellier, France; and.
authors.forename: Bernard
authors.initials: B
authors.lastname: Jover
authors.affiliation: Institut national de la santé et de la recherche médicale, Université Montpellier1, Université Montpellier2, Montpellier, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
authors.affiliation: Université d'Avignon, Avignon, France; cyril.reboul@univ-avignon.fr.
authors.forename: Cyril
authors.identifier: http://orcid.org/0000-0001-5181-3827
authors.initials: C
authors.lastname: Reboul
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002248:Carbon Monoxide / Q000633:toxicity*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056966:Excitation Contraction Coupling / Q000187:drug effects; D019570:Inhalation Exposure / Q000009:adverse effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009210:Myofibrils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000393:Air Pollutants; D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: carbon monoxide; myocardial infarction; nitric oxide; nitric oxide synthase