HMGB1-Promoted Neutrophil Extracellular Traps Contribute to Cardiac Diastolic Dysfunction in Mice

Area of Science:

• Cardiology
• Immunology
• Molecular Biology

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a growing health concern with limited treatment options.
• The specific inflammatory pathways driving HFpEF pathogenesis are not fully understood.
• Neutrophil extracellular traps (NETs) are implicated in inflammatory diseases.

Purpose of the Study:

• To investigate the role of NETs in HFpEF.
• To explore the potential therapeutic effects of targeting NETs, HMGB1, and SGLT2 inhibitors in HFpEF.

Main Methods:

• Serum and cardiac tissue analysis in HFpEF patients and a mouse model.
• Induction of HFpEF in mice via uninephrectomy, d-aldosterone, and high salt intake.
• Assessment of neutrophils, NETs, HMGB1, and cardiac function using flow cytometry, immunofluorescence, and western blotting.
• In vitro studies on neutrophil differentiation and NETs formation, investigating HMGB1 and SGLT2 inhibitors.

Main Results:

• Elevated circulating and cardiac neutrophils and NETs markers in HFpEF patients and mice.
• NETs inhibition improved cardiac inflammation, fibrosis, and diastolic function in HFpEF mice.
• Increased cardiac HMGB1 expression in HFpEF mice; HMGB1 inhibition reduced neutrophil infiltration and improved diastolic function.
• SGLT2 inhibitor empagliflozin decreased cardiac HMGB1, attenuated NETs formation, reduced fibrosis, and improved diastolic function.

Conclusions:

• NETs play a significant role in HFpEF pathogenesis.
• HMGB1 inhibition and SGLT2 inhibitors demonstrate therapeutic potential for HFpEF.
• HMGB1 and NETs represent promising novel therapeutic targets for HFpEF treatment.