Abstract 15262: Cardiac Nuclear High Mobility Group Box 1 Attenuates Angiotensin 2 Induced Pathological Cardiac Hypertrophy by Inhibiting Cardiomyocyte DNA Damage
Background: Oxidative stress leads to the cellular DNA damage. However, the mechanism by which oxidative DNA damage contributes to cardiac remodeling is unclear. High-mobility group box 1 (HMGB1) is a nuclear DNA binding protein and maintains nuclear homeostasis. The aim of this study was to investigate the role of cardiac nuclear HMGB1 in the development of pathological cardiac hypertrophy induced by angiotensin II.
Methods and Results: Cardiac nuclear HMGB1 was translocated to cytoplasm in rat neonatal cardiomyocytes after angiotensin II stimulation. HMGB1 overexpression in cardiomyocytes significantly decreased the number of γH2AX foci, a maker for DNA double-strand breaks. On the other hand, HMGB1 silencing by siRNA in cardiomyocytes increased the number of γH2AX foci. Furthermore, HMGB1 overexpression attenuated phosphorylation of ERK1/2, p38, and NFκB and HMGB1 silencing promoted phosphorylation of ERK1/2, p38, and NFκB after angiotensin II stimulation. We generated HMGB1 transgenic (Tg) mice exhibiting cardiac-specific overexpression of HMGB1. HMGB1-Tg mice and wild-type mice were treated with angiotensin II via osmotic minipumps (1.5 mg/kg/day). Cardiac hypertrophy and fibrosis were analyzed after 2 weeks of angiotensin II treatment. Cardiac hypertrophy and fibrosis were attenuated in HMGB1-Tg mice compared with wild-type mice. HMGB1 Tg mice also showed fewer γH2AX foci compared with WT mice. Furthermore, HMGB1-Tg mice showed fewer phosphorylated ataxia telangiectasia mutated protein, an upstream regulator of the DNA damage response, compared with WT mice.
Conclusions: Cardiac nuclear HMGB1 prevents angiotensin II induced cardiac hypertrophy and fibrosis by inhibiting cardiac DNA damage.
Author Disclosures: T. Takahashi: None. T. Shishido: None. T. Watanabe: None. T. Sugai: None. T. Toshima: None. M. Yokoyama: None. D. Kinoshita: None. S. Nishiyama: None. H. Takahashi: None. T. Arimoto: None. T. Miyamoto: None. T. Konta: None. I. Kubota: None.
- © 2016 by American Heart Association, Inc.