title: Neonatal asphyxia induces the nitration of cardiac myosin light chain 2 that is associated with cardiac systolic dysfunction.
abstract: Hypoxia followed by reoxygenation (H-R) observed during perinatal asphyxia is a serious complication with high mortality and morbidity rates that may cause adverse cardiovascular effects in neonates. Our aim was to determine if oxidative stress related to H-R induces peroxynitrite-dependent modifications of the cardiac contractile protein, myosin regulatory light chain 2 (MLC2), and whether this is associated with development of cardiac systolic dysfunction. Twelve newborn piglets were acutely instrumented for hemodynamic monitoring and randomized to a control group ventilated with only atmospheric air or to the H-R study group exposed to alveolar normocapnic hypoxia followed by reoxygenation. Afterward, animals were euthanized, and the hearts were harvested for biochemical analyses. Systolic function as well as cardiac MLC2 levels decreased in H-R animals, whereas nitrates and nitrotyrosine levels increased. Negative correlations between nitrates, nitrotyrosine, and MLC2 levels were observed. Moreover, H-R induced nitration of two tyrosine residues within the MLC2 protein. Similarly, in vitro exposure of MLC2 to peroxynitrite resulted in the nitration of tyrosine, which increased the susceptibility of MLC2 to subsequent degradation by matrix metalloproteinase 2. Substitution of this tyrosine with phenylalanine prevented the matrix metalloproteinase 2-dependent degradation of MLC2. In addition, a large decrease in MLC2 phosphorylation caused by H-R was observed. Oxidative stress related to asphyxia induces nitration of cardiac MLC2 protein and thus increases its degradation. This and a large decrease in MLC2 phosphorylation contribute to the development of systolic dysfunction. Inhibition of MLC2 nitration and/or direct inhibition of its degradation by MMP-2 could be potential therapeutic targets aiming at reduction of myocardial damage during resuscitation of asphyxiated newborns.
authors.affiliation: Department of Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Doroszko
authors.forename: Dorota
authors.initials: D
authors.lastname: Polewicz
authors.forename: Virgilio J J
authors.initials: VJ
authors.lastname: Cadete
authors.forename: Jolanta
authors.initials: J
authors.lastname: Sawicka
authors.forename: Michelle
authors.initials: M
authors.lastname: Jones
authors.forename: Danuta
authors.initials: D
authors.lastname: Szczesna-Cordary
authors.forename: Po-Yin
authors.initials: PY
authors.lastname: Cheung
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sawicki
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum / Q000378:metabolism*; D015153:Blotting, Western; D024722:Cardiac Myosins / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D006333:Heart Failure / Q000378:metabolism; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D007231:Infant, Newborn; D018994:Myosin Light Chains / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D013552:Swine; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018994:Myosin Light Chains; D009566:Nitrates; D009573:Nitrites; C107184:myosin light chain 2; C002744:3-nitrotyrosine; D014443:Tyrosine; D024722:Cardiac Myosins
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