Abstract 17798: Cardiac Nuclear High-Mobility Group Box 1 Attenuates Angiotensin II Induced Pathological Cardiac Hypertrophy by Inhibiting Dna Damage Response Pathway

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Abstract

Introduction: It is well-known that oxidative stress causes the cellular DNA damage. However, the mechanism by which oxidative DNA damage and following DNA damage response (DDR) contribute to cardiac remodeling is not fully elucidated. High-mobility group box 1 (HMGB1) is a nuclear DNA binding protein and reported to be associated with nuclear homeostasis and DNA repair. We previously reported that nuclear HMGB1 prevents cardiac hypertrophy and heart failure. However, the underlying mechanisms are unresolved.

Hypothesis: We investigated whether cardiac nuclear HMGB1 attenuates cardiac remodeling via inhibiting DNA damage and DDR pathway.

Methods and Results: In biopsy samples of human failing hearts, nuclear HMGB1 expression was decreased and phosphorylation of ataxia telangiectasia mutated (pATM), an upstream regulator of DDR, was increased. Immunoprecipitation revealed that HMGB1 interacted with ATM in neonatal rat cardiomyocytes (NRCM). HMGB1 overexpression in NRCM significantly inhibited the upregulation of γH2AX, a maker of DNA damage, and pATM after angiotensin II (Ang II) stimulation. Conversely, suppression of HMGB1 by siRNA exacerbated upregulation of γH2AX and pATM. Suppression of HMGB1 also increased phosphorylation of ERK 1/2 and AKT, which were attenuated by ATM inhibitor KU55933. Ang II administration in wild-type (WT) mice induced upregulation of γH2AX and pATM, and induced cardiac hypertrophy and fibrosis. These changes were attenuated in cardiac specific overexpression of HMGB1 transgenic mice. Finally, KU55933 treatment attenuated cardiac hypertrophy and fibrosis induced by Ang II in WT mice.

Conclusions: HMGB1 modulated ATM activity and prevented Ang II induced cardiac remodeling by inhibiting cardiac DNA damage and following DDR activation. Furthermore, anti-DDR treatment may be a new therapeutic strategy for cardiac remodeling.

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