Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF

Area of Science:

• Cardiovascular Research
• Mitochondrial Biology
• Metabolic Disease

Background:

• Heart failure with preserved ejection fraction (HFpEF) lacks effective disease-modifying therapies.
• The 2-hit model (high-fat diet + L-NAME) is used to study cardiometabolic HFpEF.
• C57BL6/J mice show limited diastolic dysfunction with this model, necessitating further investigation.

Purpose of the Study:

• To investigate the role of nicotinamide nucleotide transhydrogenase (NNT) in HFpEF.
• To determine if intact NNT is required for cardiac pathology in a mouse model.
• To identify potential therapeutic targets for HFpEF.

Main Methods:

• Established an isogenic model using wild-type (Nnt+/+) and NNT loss-of-function (Nnt-/-) mice on a C57BL/6N background.
• Challenged mice with a high-fat diet and L-NAME for 9 weeks.
• Assessed cardiac function via echocardiography, measured myocardial fibrosis, and analyzed metabolite levels (NAD+, GSH:GSSG) and gene expression.

Main Results:

• Nnt+/+ mice exhibited impaired diastolic relaxation, pathological remodeling, and increased myocardial fibrosis.
• Significant reductions in NAD+ and the GSH:GSSG ratio were observed in Nnt+/+ mice.
• Single-nucleus ligand-receptor analysis implicated fibroblast growth factor 1 (Fgf1) as an NNT-dependent mediator.

Conclusions:

• Mitochondrial dysfunction, specifically involving NNT, is crucial in HFpEF pathogenesis.
• NNT and Fgf1 emerge as novel therapeutic targets for treating HFpEF.
• This study provides critical insights into the molecular mechanisms underlying HFpEF.