Nitro-oleic acid enhances mitochondrial metabolism and ameliorates heart failure with preserved ejection fraction in mice
The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunction contribute to HFpEF. Nitro-oleic acid (NO<sub>2</sub>-OA) impacts metabolic syndromes by improving glucose tolerance and adipocyte function. Here we show that treatment with NO<sub>2</sub>-OA ameliorates diastolic dysfunction and heart failure symptoms in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. Proteomic analysis of left ventricular tissue reveals that one-third of identified proteins, predominantly mitochondrial, are upregulated in hearts of NO<sub>2</sub>-OA-treated HFpEF mice compared to naïve and vehicle-treated HFpEF mice. Increased mitochondrial mass and numbers, and enhanced mitochondrial respiration are linked with this response, as assessed by transmission electron microscopy and high-resolution respirometry. Activation of the 5'-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediates the enhancement of mitochondrial dynamics in hearts of NO<sub>2</sub>-OA-treated HFpEF mice. These findings suggest that targeting mitochondrial function with NO<sub>2</sub>-OA may represent a promising therapeutic strategy for HFpEF.
Authors
- Uwe Schlomann
- Kristina Lorenz (ORCID: https://orcid.org/0000-0002-5747-2207)
- Volker Rudolph (ORCID: https://orcid.org/0000-0001-5385-6839)
- Bruce Α. Freeman (ORCID: https://orcid.org/0000-0002-2028-8369)
- Elfi Donhauser (ORCID: https://orcid.org/0009-0003-1395-0398)
- Tamino Huxohl (ORCID: https://orcid.org/0000-0001-8865-2895)
- Sven Heiles (ORCID: https://orcid.org/0000-0003-3779-8071)
- Johann Dierks
- Simon Lüdtke
- Thomas Patschkowski
- Torben Schubert (ORCID: https://orcid.org/0000-0001-9546-880X)
- Jurek Hense
- Bernd Stratmann (ORCID: https://orcid.org/0000-0001-5777-3715)
- Vasco Sequeira (ORCID: https://orcid.org/0000-0002-9192-7674)
- Francisco J. Schöpfer (ORCID: https://orcid.org/0000-0001-9526-695X)
- Jacqueline Heinen‐Weiler
- Jan‐Christian Reil (ORCID: https://orcid.org/0000-0003-1053-5175)
- Elen Tolstik (ORCID: https://orcid.org/0000-0003-0873-4335)
- Luisa Andrea Lengenfelder
- Cornelius Bischof (ORCID: https://orcid.org/0000-0001-8496-2853)
- Martina Düfer (ORCID: https://orcid.org/0000-0003-1572-9235)
- Tibor Maske
- Felix-Levin Hormann (ORCID: https://orcid.org/0009-0006-3784-6124)
- Lucia Landwehrjohann
- Anna Klinke (ORCID: https://orcid.org/0000-0002-1118-4082)
- Marion Müller (ORCID: https://orcid.org/0000-0002-8519-0661)
- Tina Johanna Schulz
- Elisa Theres Vogt
Institutions
- University of Pittsburgh (US)
- Bielefeld University (DE)
- University of Münster (DE)
- University of Würzburg (DE)
- Heart and Diabetes Center North Rhine-Westphalia (DE)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Universitätsklinikum Würzburg (DE)
- University of Duisburg-Essen (DE)
- Ruhr University Bochum (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-26
- DOI
- https://doi.org/10.1038/s41467-025-59192-5
- Citations
- 6
- Primary Topic
- Cardiovascular Function and Risk Factors
- Type
- article
- Field-Weighted Citation Impact
- 8.33
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Deutsche Stiftung für Herzforschung
- Deutsche Diabetes Gesellschaft
- Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen
- National Institutes of Health
- Leibniz-Gemeinschaft