Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF

Area of Science:

• Cardiovascular Disease Research
• Mitochondrial Biology
• Metabolic Disorders

Background:

• Heart failure with preserved ejection fraction (HFpEF) affects over 50% of heart failure patients.
• The complex pathophysiology and lack of suitable animal models hinder effective HFpEF therapies.

Purpose of the Study:

• To investigate the metabolic mechanisms underlying HFpEF.
• To test therapeutic interventions for HFpEF using a novel mouse model.

Main Methods:

• Developed a novel mouse model mimicking HFpEF features through aging, high-fat diet, and desoxycorticosterone pivalate challenge.
• Investigated the role of mitochondrial hyperacetylation and inflammation in HFpEF pathogenesis.
• Assessed the therapeutic potential of increasing beta-hydroxybutyrate levels.

Main Results:

• Mitochondrial hyperacetylation exacerbated HFpEF phenotypes in the mouse model.
• Increased beta-hydroxybutyrate availability rescued HFpEF phenotypes, attenuated inflammasome activation (NLRP3), and reduced tissue fibrosis.
• Beta-hydroxybutyrate reduced the acetyl-CoA pool and mitochondrial acetylation, partly via citrate synthase activation.

Conclusions:

• Mitochondrial hyperacetylation and inflammation are key drivers of HFpEF.
• Promoting beta-hydroxybutyrate abundance offers a potential therapeutic strategy for HFpEF.