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Cardioprotective mechanism of S-nitroso-N-acetylcysteine via S-nitrosated betadrenoceptor-2 in the LDLr-/- mice.

Abstract
Previous studies from our group have demonstrated the protective effect of S-nitroso-N-acetylcysteine (SNAC) on the cardiovascular system in dyslipidemic LDLr-/- mice that develop atheroma and left ventricular hypertrophy after 15 days on a high fat diet. We have shown that SNAC treatment attenuates plaque development via the suppression of vascular oxidative stress and protects the heart from structural and functional myocardial alterations, such as heart arrhythmia, by reducing cardiomyocyte sensitivity to catecholamines. Here we investigate the ability of SNAC to modulate oxidative stress and cell survival in cardiomyocytes during remodeling and correlation with β₂-AR signaling in mediating this protection. Ventricular superoxide (O₂⁻) and hydrogen peroxide (H₂O₂) generation was measured by HPLC methods to allow quantification of dihydroethidium (DHE) products. Ventricular histological sections were stained using terminal dUTP nick-end labeling (TUNEL) to identify nuclei with DNA degradation (apoptosis) and this was confirmed by Western blot for cleaved caspase-3 and caspase-7 protein expression. The findings show that O₂⁻ and H₂O₂ production and also cell apoptosis were increased during left ventricular hypertrophy (LVH). SNAC treatment reduced oxidative stress during on cardiac remodeling, measured by decreased H₂O₂ and O₂⁻ production (65% and 52%, respectively), and a decrease in the ratio of p-Ser1177 eNOS/total eNOS. Left ventricle (LV) from SNAC-treated mice revealed a 4-fold increase in β₂-AR expression associated with coupling change to Gi; β₂-ARs-S-nitrosation (β₂-AR-SNO) increased 61%, while apoptosis decreased by 70%. These results suggest that the cardio-protective effect of SNAC treatment is primarily through its anti-oxidant role and is associated with β₂-ARs overexpression and β₂-AR-SNO via an anti-apoptotic pathway.
AuthorsAmarylis Claudine Bonito Azeredo Wanschel, Viviane Menezes Caceres, Ana Iochabel Soares Moretti, Alexandre Bruni-Cardoso, Hernandes Faustino de Carvalho, Heraldo Possolo de Souza, Francisco Rafael Martins Laurindo, Regina Célia Spadari, Marta Helena Krieger
JournalNitric oxide : biology and chemistry (Nitric Oxide) Vol. 36 Pg. 58-66 (Jan 30 2014) ISSN: 1089-8611 [Electronic] United States
PMID24333561 (Publication Type: Journal Article)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Antioxidants
  • Reactive Oxygen Species
  • Receptors, Adrenergic, beta-2
  • Receptors, LDL
  • Superoxides
  • S-nitroso-N-acetylcysteine
  • Hydrogen Peroxide
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Nitrogen
  • Acetylcysteine
Topics
  • Acetylcysteine (analogs & derivatives, pharmacology)
  • Animals
  • Antioxidants (pharmacology)
  • Apoptosis
  • Dyslipidemias
  • Endoplasmic Reticulum (metabolism)
  • Gene Expression Regulation
  • Hydrogen Peroxide (chemistry)
  • Hypertrophy, Left Ventricular
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac (cytology)
  • Nitric Oxide Synthase Type III (metabolism)
  • Nitrogen (metabolism)
  • Oxidative Stress
  • Reactive Oxygen Species (metabolism)
  • Receptors, Adrenergic, beta-2 (genetics)
  • Receptors, LDL (genetics)
  • Superoxides

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