FINAL ACCEPTED VERSION

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 if the mitogen-activated protein kinase (MAPK) signal transduction pathways are involved in the oxidative stress-induced myocyte apoptosis. Rabbits with rapid pacing induced CHF and sham operation were randomized to receive either a combination of antioxidant vitamins (β-carotene, ascorbic acid and α-tocopherol), α-tocopherol alone, or placebo for eight weeks. Compared to the sham-operated animals, the 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 per 10,000 cardiomyocytes, P<0.05), increased total and phosphorylated c-Jun N-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-regulated kinase (p-ERK). Administration of antioxidant vitamins and α-tocopherol attenuated oxidative stress