Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-a and angiotensin II

Background-Tumor necrosis factor-alpha (TNF-alpha) and angiotensin II (Ang II) modulate heart failure in part by provoking the hypertrophic response. Signal transduction pathways of those factors are implicated in reactive oxygen intermediates (ROIs), Therefore, we hypothesized that TNF-alpha and Ang Il might cause myocyte hypertrophy via the generation of ROIs. Methods and Results-To test the hypothesis, we tested whether TNF-alpha and Ang II could induce the generation of ROIs and whether antioxidants such as butylated hydroxyanisole (BHA), vitamin E, and catalase might inhibit the hypertrophy in cultured neonatal rat cardiac myocytes. ROIs were measured by the ROI-specific probe 2',7'-dichlorofluorescin diacetate in cultured cardiac myocytes. We demonstrated that TNF-alpha and Ang II induced the generation of ROIs in a dose-dependent manner. TNF-alpha (10 ng/mL) and Ang II (100 nmol/L) enlarged cardiac myocytes and increased [H-3]leucine uptake, and BHA (10 mu mol/L) significantly inhibited both effects. Other antioxidants, such as vitamin E (1 mu g/mL) and catalase (100 U/mL), also inhibited the enlargement of cardiac myocytes induced by TNF-alpha. Conclusions-These results indicate that TNF-alpha and Ang II cause hypertrophy in part via the generation of ROIs in cardiac myocytes.