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Am J Physiol Heart Circ Physiol. 2015 Apr 1;308(7):H759-67. doi: 10.1152/ajpheart.00702.2014. Epub 2015 Jan 16.

Carbon monoxide increases inducible NOS expression that mediates CO-induced myocardial damage during ischemia-reperfusion.

Author information

1
Université d'Avignon, Avignon, France;
2
Institut national de la santé et de la recherche médicale, Université Montpellier1, Université Montpellier2, Montpellier, France;
3
Fédération de Médecine Translationelle, Faculty of Medicine, Université de Strasbourg, Strasbourg France;
4
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.
5
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.
6
Centre de Pharmacologie et Innovation dans le Diabète, Faculty of Pharmacy, Université Montpellier1, Montpellier, France; and.
7
Université d'Avignon, Avignon, France; cyril.reboul@univ-avignon.fr.

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.

KEYWORDS:

carbon monoxide; myocardial infarction; nitric oxide; nitric oxide synthase

PMID:
25595132
DOI:
10.1152/ajpheart.00702.2014
[Indexed for MEDLINE]
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