title: Antioxidants attenuate myocyte apoptosis and improve cardiac function in CHF: association with changes in MAPK pathways.
abstract: Antioxidant vitamins reduce cardiac oxidative stress and cardiomyocyte apoptosis produced by exogenous norepinephrine (NE) and attenuate cardiac dysfunction in animals with pacing-induced congestive heart failure (CHF). This study was carried out to determine whether the mitogen-activated protein kinase (MAPK) signal transduction pathways are involved in oxidative stress-induced myocyte apoptosis. Rabbits with rapid pacing-induced CHF and sham operation were randomized to receive either a combination of antioxidant vitamins (beta-carotene, ascorbic acid, and alpha-tocopherol), alpha-tocopherol alone, or placebo for 8 wk. Compared with sham-operated animals, CHF animals exhibited increased oxidative stress as evidenced by decreased myocardial reduced-to-oxidized glutathione (GSH/GSSG) ratio (27 +/- 7 vs. 143 +/- 24, P < 0.05), myocyte apoptosis (77 +/- 18 vs. 17 +/- 4 apoptotic nuclei/10,000 cardiomyocytes, P < 0.05), increased total and phosphorylated c-Jun NH2-terminal protein kinase (p-JNK; 1.95 +/- 0.14 vs. 1.04 +/- 0.04 arbitrary units, P < 0.05) and phosphorylated p38 kinase (p-p38), and decreased phosphorylated extracellular signal-regulated kinase (p-ERK). Administration of antioxidant vitamins and alpha-tocopherol attenuated oxidative stress, myocyte apoptosis, and cardiac dysfunction, with reversal of the changes of total JNK, p-JNK, and p-ERK in CHF. Furthermore, because NE infusion produced changes of JNK, p-p38, and p-ERK similar to those in CHF, we conclude that NE may play an important role in the production of oxidative stress, MAPK activation, and myocyte apoptosis in CHF.
authors.affiliation: Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Box 679, 601 Elmwood Avenue, Rochester, NY 14642, USA. fuzhong_qin@urmc.rochester.edu
authors.forename: Fuzhong
authors.initials: F
authors.lastname: Qin
authors.forename: Junya
authors.initials: J
authors.lastname: Shite
authors.forename: Chang-seng
authors.initials: CS
authors.lastname: Liang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D002839:Chromans / Q000494:pharmacology; D004277:DNA, Single-Stranded / Q000276:immunology; D005978:Glutathione / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011817:Rabbits; D013482:Superoxide Dismutase / Q000494:pharmacology; D013566:Sympathomimetics / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology*; D019207:beta Carotene / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000911:Antibodies, Monoclonal; D000975:Antioxidants; D002839:Chromans; D004277:DNA, Single-Stranded; D013566:Sympathomimetics; D019207:beta Carotene; D013482:Superoxide Dismutase; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D024502:alpha-Tocopherol; D001205:Ascorbic Acid; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D009638:Norepinephrine