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.

Importance of antioxidant and antiapoptotic effects of β-receptor blockers in heart failure therapy

“…However, the effects of carvedilol and metoprolol on left ventricular end-diastolic pressure were relatively smaller and not statistically significant, given the number of animals studied, and there were no significant differences of peak left ventricular dP/dt at rest among the four experimental CHF groups. Discrepancies in the magnitude of changes in cardiac function as measured by the echocardiography and cardiac catheterization have been described before (17,35). We speculate that the difference between the two states may be related to the different levels of anesthesia used.…”

“…Reduction of myocyte apoptosis also has been shown with antioxidant vitamins in CHF animals (35). However, ␤-receptor blockade may play an important role in the antiapoptotic effect as well, because propranolol plus doxazosin, which had no major effect on cardiac oxidative stress, produced a reduction of myocyte apoptosis in CHF.…”

“…One week after surgery, rabbits were randomly assigned to receive either pacing at a rate of 340 beats/min with a model 8086 Prevail implantable programmable pacemaker modified for rapid pacing (Medtronic, Minneapolis, MN) (CHF animals) or no cardiac pacing (sham animals). The animals developed progressive heart failure beginning 1-2 wk after start of rapid ventricular pacing (16) and evidence of oxidative stress and myocyte apoptosis after 8 wk of pacing (35).…”

“…This antioxidant effect of carvedilol may be clinically important because oxygen free radicals, which have been shown to increase in heart failure (43), can cause myocyte apoptosis (4), myocardial ␤-adrenergic receptor signal transduction abnormalities (21), and contractile dysfunction (6). In a recent study (35), we report that left ventricular mechanical function improved with antioxidant vitamins in animals with tachypacing-induced cardiomyopathy. In addition, antioxidant vitamins reduced the proapoptotic-to-antiapoptotic protein ratio and myocyte apoptosis in the CHF animals (42).…”

Rationale, Design, and Organization of the Diastolic Heart Failure Assessment Study in Tohoku District (DIAST)

“…26 Antioxidants attenuate LV hypertrophy 27,28 and apoptosis. 29 LV hypertrophy and myocardial fibrosis caused by apoptosis increase the stiffness leading to diastolic dysfunction. Therefore, the antioxidant effect of carvedilol 30 may exert a beneficial effect in DHF and thus the results of numerous experiments suggest the potential benefit of -blockers for impaired diastolic function.…”