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| Item Type: | Article |
|---|---|
| Title: | Murine metabolic HFpEF is associated with altered mitochondrial substrate handling and S-nitrosylation remodeling |
| Creators: |
Li, Huihui, Cui, Hanyu, Wang, Daiyu, Leuschner, Florian, Heineke, Joerg  ORCID: https://orcid.org/0000-0002-1541-3030, Hu, Jiong and Bibli, Sofia-Iris ORCID: https://orcid.org/0000-0001-7153-6628
|
| Abstract: | Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition with incompletely defined myocardial mechanisms. Here, using a two-hit murine model of cardiometabolic HFpEF induced by high-fat diet and endothelial nitric oxide synthase inhibition, we define a mitochondrial metabolic phenotype characterized by altered substrate handling, redox stress, and S-nitrosylation remodeling. While global proteomic changes were modest, metabolomic profiling revealed selective remodeling of tricarboxylic acid cycle intermediates, increased dicarboxylic acids, and altered redox-associated metabolites, consistent with mitochondrial metabolic and redox imbalance in this experimental setting. S-nitrosylation proteomics demonstrated a highly organized and bidirectional remodeling pattern affecting proteins involved in fatty acid/lipid metabolism, carbohydrate metabolism, mitochondrial energy metabolism, amino acid and organic acid metabolism, nucleotide/co-factor metabolism, and redox defense. Stable isotope tracing showed reduced glucose-derived and increased palmitate-derived acetyl-CoA in HFpEF, whereas Na-βHB reduced palmitate contribution and increased βHB-derived acetyl-CoA without restoring glucose contribution, indicating substrate redistribution and preserved ketone oxidation. Na-βHB supplementation increased oligomycin-sensitive respiration in freshly prepared left ventricular tissue, partially normalized selected TCA-cycle intermediates, reduced mitochondrial ROS and the NADH/NAD(+) ratio, restored the GSH/GSSG ratio, and improved diastolic function without altering ejection fraction. Together, these findings define a redox-sensitive mitochondrial metabolic state in the HFD/l-NAME model and identify ketone supplementation as a partial metabolic rescue strategy in this context. At the same time, these findings highlight an important limitation of the murine HFD/l-NAME model, which should be interpreted as an experimental system for studying high-fat-induced cardiometabolic stress rather than as a metabolic equivalent of human HFpEF. |
| Keywords: | Animals, Mice |
| Source: | Redox Biology |
| ISSN: | 2213-2317 |
| Publisher: | Elsevier |
| Volume: | 96 |
| Page Range: | 104349 |
| Date: | October 2026 |
| Official Publication: | https://doi.org/10.1016/j.redox.2026.104349 |
| PubMed: | View item in PubMed |
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