Abstract 16074: The Role of Nuclear Nox4 in Mediating Oxidation of HDAC4 in Response to Phenylephrine Stimulation
INTRODUCTION: Reduction and oxidation are critically involved in the pathogenesis of cardiac hypertrophy and heart failure. Oxidation of conserved cysteine residues in histone deacetylase 4 (HDAC4) induces cytoplasmic translocation of HDAC4, thereby mediating phenylephrine (PE)-induced cardiac hypertrophy. NAD(P)H oxidase 4 (Nox4) is a major source of oxidative stress in cardiomyocytes (CMs) in response to pressure overload.
HYPOTHESIS: We hypothesized that Nox4 plays an essential role in mediating cardiac hypertrophy by regulating the redox state of HDAC4.
METHOD AND RESULTS: Nox4 exists on intracellular membranes, including those of the mitochondria and nucleus, in CMs. A subpressor dose of PE (20 mg/kg per day) or saline alone (control) was continuously infused into wild type (WT) and cardiac specific Nox4 knockout (Nox4-/-) mice subcutaneously via an osmotic minipump. After 14 days, mean aortic pressure was similar in WT and Nox4-/- mice. Left ventricular (LV) wall thickness (1.04±0.03 vs. 1.27±0.06 mm, p<0.05) and LV weight/ tibial length (LVW/TL, 5.7±0.14 vs. 6.4±0.05 mg/mm, p<0.05) were significantly lower in Nox4-/- than in WT mice. CM cross sectional area (MCA: 223±13 vs. 258±12 μm2, p<0.05) was significantly smaller in Nox4-/- than in WT mice. O2- production from the nuclear membrane, as evaluated by lucigenin chemiluminescent assays, was also significantly lower in Nox4-/- than in WT mice (4116±314 vs. 7057±1710 RLU, p<0.05). On the other hand, PE infusion induced significantly greater cardiac hypertrophy in transgenic mice with cardiac specific overexpression of Nox4 than in control mice. In cultured neonatal rat CMs, PE (100μM) treatment induced upregulation of Nox4 (2.8 fold vs. control, p<0.05) within 5 min, which was accompanied by increases in O2- production (6 fold, p<0.01) and rapid (< 5min) nuclear export of HDAC4. Knockdown of Nox4 with shRNA-Nox4, but not Nox2 knockdown, attenuated O2- production in the nucleus and prevented PE-induced oxidation and nuclear export of HDAC4.
CONCLUSIONS: Nox4 plays an essential role in mediating PE-induced cardiac hypertrophy. Nox4 mediates PE-induced O2- production in the nucleus and nuclear export of HDAC4 through cysteine oxidation.
- © 2011 by American Heart Association, Inc.