Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction

Area of Science:

• Cardiology
• Metabolic Disorders
• Molecular Biology

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a significant clinical challenge.
• Hypertension and obesity-related metabolic disorders are key comorbidities in HFpEF.
• The interaction between mechanical overload and metabolic issues in HFpEF pathogenesis is not well understood.

Purpose of the Study:

• To investigate the mechanisms of HFpEF development under combined mechanical and metabolic stress.
• To identify key molecular pathways involved in HFpEF pathogenesis.
• To evaluate potential therapeutic targets for HFpEF.

Main Methods:

• Utilized a mouse model combining transverse aortic constriction (pressure overload) with genetic obesity/diabetes.
• Employed single-nuclei RNA sequencing to analyze cardiomyocyte transcriptomes.
• Tested the efficacy of glucagon receptor antagonism and genetic deletion.

Main Results:

• Obese/diabetic mice with pressure overload developed HFpEF features, unlike lean mice which showed heart failure with reduced ejection fraction.
• Single-nuclei RNA-seq revealed distinct transcriptional changes in cardiomyocytes under combined stress.
• Glucagon signaling was identified as a key pathway, and its antagonism ameliorated HFpEF progression.

Conclusions:

• Glucagon receptor signaling in cardiomyocytes is crucial for HFpEF progression.
• Targeting the glucagon receptor presents a promising therapeutic strategy for HFpEF.
• This study provides a preclinical basis for developing glucagon receptor antagonists for HFpEF treatment.