Cardiac Nuclear High-Mobility Group Box 1 Ameliorates Pathological Cardiac Hypertrophy by Inhibiting...

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• High-mobility group box 1 (HMGB1) is a DNA-binding protein involved in DNA repair.
• Reduced nuclear HMGB1 and elevated DNA damage response (DDR) characterize human failing hearts.
• HMGB1 plays a crucial role in maintaining cardiac health and function.

Purpose of the Study:

• To investigate the role of HMGB1 in cardiac remodeling and DNA damage response.
• To explore the cardioprotective effects of modulating HMGB1 and DDR pathways.
• To understand the molecular mechanisms underlying HMGB1-mediated cardiac protection.

Main Methods:

• Utilized cardiac-specific HMGB1 overexpression transgenic mice and wild-type littermates.
• Administered angiotensin II to induce cardiac remodeling and DNA damage.
• Performed in vitro experiments inhibiting HMGB1 and treating with DDR inhibitors.
• Assessed DNA damage, DDR markers, cardiac remodeling, and signaling pathways (ERK1/2, NF-κB).

Main Results:

• Cardiac-specific HMGB1 overexpression suppressed DNA damage, DDR, and cardiac remodeling post-angiotensin II stimulation.
• Inhibition of HMGB1 in vitro increased extracellular signal-related kinase 1/2 (ERK1/2) and nuclear factor kappa B (NF-κB) phosphorylation.
• DDR inhibitor treatment rescued HMGB1 inhibition-induced signaling changes.
• DDR inhibitor treatment demonstrated cardioprotective effects against angiotensin II-induced cardiac remodeling.

Conclusions:

• HMGB1 plays a protective role against cardiac remodeling and DNA damage.
• Modulating HMGB1 and DDR pathways offers a potential therapeutic strategy for heart failure.
• Targeting DDR pathways can mitigate angiotensin II-induced cardiac injury.