Nitro-oleic acid enhances mitochondrial metabolism and ameliorates heart failure with preserved ejection fraction in mice

Marion Müller, Torben Schubert, Cornelius Welke, Tibor Maske, Thomas Patschkowski, Elfi Donhauser, Jacqueline Heinen-Weiler, Felix-Levin Hormann, Sven Heiles, Tina Johanna Schulz, Luisa Andrea Lengenfelder, Lucia Landwehrjohann, Elisa Theres Vogt, Bernd Stratmann, Jurek Hense, Simon Lüdtke, Martina Düfer, Elena Tolstik, Johann Dierks, Kristina Lorenz, Tamino Huxohl, Jan-Christian Reil, Vasco Sequeira, Francisco Jose Schopfer, Bruce A. Freeman, Volker Rudolph, Uwe Schlomann and Anna Klinke ()
Additional contact information
Marion Müller: Ruhr-Universität Bochum
Torben Schubert: Ruhr-Universität Bochum
Cornelius Welke: Ruhr-Universität Bochum
Tibor Maske: Ruhr-Universität Bochum
Thomas Patschkowski: Bielefeld University
Elfi Donhauser: Ruhr-Universität Bochum
Jacqueline Heinen-Weiler: Ruhr-Universität Bochum
Felix-Levin Hormann: Leibniz-Institut für Analytische Wissenschaften-ISAS e.V.
Sven Heiles: Leibniz-Institut für Analytische Wissenschaften-ISAS e.V.
Tina Johanna Schulz: Ruhr-Universität Bochum
Luisa Andrea Lengenfelder: Ruhr-Universität Bochum
Lucia Landwehrjohann: Ruhr-Universität Bochum
Elisa Theres Vogt: Ruhr-Universität Bochum
Bernd Stratmann: Ruhr-Universität Bochum
Jurek Hense: University of Münster
Simon Lüdtke: University of Münster
Martina Düfer: University of Münster
Elena Tolstik: Leibniz-Institut für Analytische Wissenschaften-ISAS e.V.
Johann Dierks: Leibniz-Institut für Analytische Wissenschaften-ISAS e.V.
Kristina Lorenz: Leibniz-Institut für Analytische Wissenschaften-ISAS e.V.
Tamino Huxohl: Ruhr-Universität Bochum
Jan-Christian Reil: Ruhr-Universität Bochum
Vasco Sequeira: DZHI
Francisco Jose Schopfer: University of Pittsburgh
Bruce A. Freeman: University of Pittsburgh
Volker Rudolph: Ruhr-Universität Bochum
Uwe Schlomann: Ruhr-Universität Bochum
Anna Klinke: Ruhr-Universität Bochum

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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 (NO2-OA) impacts metabolic syndromes by improving glucose tolerance and adipocyte function. Here we show that treatment with NO2-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 NO2-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 NO2-OA-treated HFpEF mice. These findings suggest that targeting mitochondrial function with NO2-OA may represent a promising therapeutic strategy for HFpEF.

Date: 2025
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DOI: 10.1038/s41467-025-59192-5

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