Enhanced cardiac mitochondrial biogenesis by nitro-oleic acid remedies diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction

Mueller, M.; Schubert, T.; Welke, C.; Schulz, T. J.; Patschkowski, T.; Maske, T.; Lengenfelder, L. A.; Landwehrjohann, L.; Donhauser, E.; Vogt, E. T.; Stratmann, B.; Hense, J.; Luedtke, S.; Duefer, M.; Tolstik, E.; Dierks, J.; Hormann, F.-L.; Heiles, S.; Lorenz, K.; Reil, J.-C.; Schopfer, F. J.; Freeman, B. A.; Rudolph, V.; Schlomann, U.; Klinke, A.

doi:10.1101/2024.02.20.581137

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bioRxiv · 10.1101/2024.02.20.581137

Enhanced cardiac mitochondrial biogenesis by nitro-oleic acid remedies diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction

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Abstract

Prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunctions contribute to HFpEF progression. Nitro-oleic acid (NO2-OA) impacts metabolic processes by improving glucose tolerance and adipocyte function. In this study, 4 week treatment with NO2-OA ameliorated diastolic dysfunction in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. A proteomic analysis of left ventricular tissue revealed, that one third of the identified proteins, mostly mitochondrial proteins, were upregulated in hearts of NO2-OA-treated HFpEF mice compared to controls and vehicle-treated HFpEF mice, which was confirmed by immunoblot. Activation of the 5-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediated an enhancement of mitochondrial biogenesis in hearts of NO2-OA-treated HFpEF mice. In cardiomyocytes under metabolic stress, NO2-OA increased mitochondrial protein level accompanied by enhanced oxidative phosphorylation. In conclusion, targeting mitochondrial integrity in HFpEF leads to improved diastolic function.

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Mueller, M., Schubert, T., Welke, C., Schulz, T. J., Patschkowski, T., Maske, T., Lengenfelder, L. A., Landwehrjohann, L., Donhauser, E., Vogt, E. T., Stratmann, B., Hense, J., Luedtke, S., Duefer, M., Tolstik, E., Dierks, J., Hormann, F.-L., Heiles, S., Lorenz, K., Reil, J.-C., Schopfer, F. J., Freeman, B. A., Rudolph, V., Schlomann, U., Klinke, A.. 2024-02-22. Enhanced cardiac mitochondrial biogenesis by nitro-oleic acid remedies diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction. https://doi.org/10.1101/2024.02.20.581137

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