Increased Oxidative Stress in the Nucleus Caused by Nox4 Mediates Oxidation of HDAC4 and Cardiac Hypertrophy
Rationale: Oxidation of cysteine residues in class II histone deacetylases (HDACs), including HDAC4, causes nuclear exit, thereby inducing cardiac hypertrophy. The cellular source of reactive oxygen species (ROS) responsible for oxidation of HDAC4 remains unknown.
Objective: We investigated whether Nox4, a major NADPH oxidase, mediates cysteine oxidation of HDAC4.
Methods and Results: Phenylephrine (PE, 100 µM), an α1 adrenergic agonist, induced upregulation of Nox4 (1.5-fold, p<0.05) within 5 min, accompanied by increases in O2- (3.5-fold, p<0.01) from the nuclear membrane and nuclear exit of HDAC4 in cardiomyocytes (CM). Knockdown of Nox4, but not Nox2, attenuated O2- production in the nucleus and prevented PE-induced oxidation and nuclear exit of HDAC4. After continuous infusion of PE (20 mg/kg/day) for 14 days, wild-type (WT) and cardiac-specific Nox4 knockout (c-Nox4 KO) mice exhibited similar aortic pressures. Left ventricular (LV) weight/ tibial length (5.7±0.2 vs. 6.4±0.2 mg/mm, p<0.05) and CM cross-sectional area (223±13 vs. 258±12 µm2, p<0.05) were significantly smaller in c-Nox4 KO than in WT mice. Nuclear O2- production in the heart was significantly lower in c-Nox4 KO than in WT mice (4116±314 vs. 7057±1710 RLU, p<0.05), and cysteine oxidation of HDAC4 was decreased. HDAC4 oxidation and cardiac hypertrophy were also attenuated in c-Nox4 KO mice 2 weeks after transverse aortic constriction.
Conclusions: Nox4 plays an essential role in mediating cysteine oxidation and nuclear exit of HDAC4, thereby mediating cardiac hypertrophy in response to PE and pressure overload.
- Received August 14, 2012.
- Accepted December 27, 2012.
- Copyright © 2012, American Heart Association