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Antioxidants attenuate myocyte apoptosis and improve cardiac function in CHF: association with changes in MAPK pathways

Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642

Submitted 7 January 2003 ; accepted in final form 16 April 2003

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 (-carotene, ascorbic acid, and -tocopherol), -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 -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.

congestive heart failure; signal transduction; norepinephrine; oxidative stress; mitogen-activated protein kinase

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