Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3.

Area of Science:

• Cardiovascular disease research
• Hepatology
• Epigenetics

Background:

• High salt intake is a major risk factor for cardiovascular diseases (CVDs).
• Nonalcoholic fatty liver disease (NAFLD) is linked to high salt intake and is an independent CVD risk factor.
• The direct link between salt-induced liver damage and CVD development remains unclear.

Purpose of the Study:

• To investigate if salt-induced hepatic damage contributes to cardiovascular disease development.
• To elucidate the molecular mechanisms underlying persistent liver inflammation and CVD under high salt conditions.
• To evaluate the therapeutic potential of metformin in mitigating salt-induced damage.

Main Methods:

• Mice were fed high-salt or normal diets for 8 weeks.
• Salt withdrawal and metformin treatment were applied to high-salt fed mice.
• Gene expression, knockout models (SIRT3, NRF2, AMPK), and epigenetic analysis (H3K27ac) were utilized.

Main Results:

• High salt diet induced hepatic steatosis, inflammation, hypertension, and cardiac dysfunction in mice.
• These pathological changes showed a persistent 'memory phenomenon' after salt withdrawal.
• Reduced sirtuin 3 (SIRT3) expression, due to histone modification (H3K27ac) inhibiting NRF2 binding, was identified as the cause of persistent inflammation and CVD.
• Metformin activated AMPK, reduced H3K27ac, restored NRF2 binding, increased SIRT3 expression, and reversed hepatic inflammation and CVD.

Conclusions:

• SIRT3 inhibition via histone modification is critical for persistent liver damage and CVD under high salt intake.
• Interventions targeting epigenetic modifications, alongside salt restriction, may prevent sustained inflammation and CVD.
• Maintaining adequate SIRT3 expression is crucial for mitigating high-salt-induced cardiovascular risks.