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Linoleic Acid Metabolite DiHOME Decreases Post-ischemic Cardiac Recovery in Murine Hearts

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Abstract

Cardiac ischemia/reperfusion injury is associated with the formation and action of lipid mediators derived from polyunsaturated fatty acids. Among them, linoleic acid (LA) is metabolized to epoxyoctadecanoic acids (EpOMEs) by cytochrome P450 (CYP) epoxygenases and further to dihydroxyoctadecanoic acids (DiHOMEs) by soluble epoxide hydrolase (sEH). We hypothesized that EpOMEs and/or DiHOMEs may affect cardiac post-ischemic recovery and addressed this question using isolated murine hearts in a Langendorff system. Hearts from C57Bl6 mice were exposed to 12,13-EpOME, 12,13-DiHOME, or vehicle (phosphate buffered sodium; PBS). Effects on basal cardiac function and functional recovery during reperfusion following 20 min of ischemia were investigated. Electrocardiogram (ECG), left ventricular (LV) pressure and coronary flow (CF) were continuously measured. Ischemia reperfusion experiments were repeated after administration of the sEH-inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA). At a concentration of 100 nM, both EpOME and DiHOME decreased post-ischemic functional recovery in murine hearts. There was no effect on basal cardiac parameters. The detrimental effects seen with EpOME, but not DiHOME, were averted by sEH inhibition (AUDA). Our results indicate that LA-derived mediators EpOME/DiHOME may play an important role in cardiac ischemic events. Inhibition of sEH could provide a novel treatment option to prevent detrimental DiHOME effects in acute cardiac ischemia.

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Abbreviations

AUDA:

12-(3-Adamantan-1-yl-ureido)dodecanoic acid

CF:

Coronary flow

CYP:

Cytochrome P450

DiHOME:

Dihydroxyoctadecanoic acid

EET:

Epoxyeicosatrienoic acid

EpOME:

Epoxyoctadecanoic acid

HR:

Heart rate

LA:

Linoleic acid

LV:

Left ventricle

LVdia:

Left ventricular diastolic pressure

LVDP:

Left ventricular developed pressure

PBS:

Phosphate-buffered sodium

sEH:

Soluble epoxide hydrolase

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Acknowledgements

In this work results of the dissertation “Effekte der Linolsäurederivate 12,13-Epoxyoctadecensäure(-methylester) und 12,13-Dihydroxyoctadecensäure(-methylester) auf das isolierte murine Herz” by Marwin Bannehr submitted in 2019 to Charité - Universitätsmedizin Berlin have been included. The authors thank Bastian Spallek, Michael Gotthardt and Ingo Morano for technical support and assistance during the experiments.

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Author notes

  1. Maik Gollasch and Alexander Wutzler are equal senior authors.

Authors and Affiliations

  1. Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany

    Marwin Bannehr, Lena Löhr, Julia Gelep & Wilhelm Haverkamp

  2. Max-Delbrück-Center for Molecular Medicine, 16341, Berlin, Germany

    Wolf-Hagen Schunck

  3. Experimental and Clinical Research Center, 16341, Berlin, Germany

    Maik Gollasch & Alexander Wutzler

  4. Department of Nephrology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany

    Maik Gollasch

  5. Department of Electrophysiology and Cardiac Rhythm Management, St. Joseph Hospital, Ruhr-University Bochum, 44791, Bochum, Germany

    Alexander Wutzler

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  1. Marwin Bannehr
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Correspondence to Marwin Bannehr.

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Bannehr, M., Löhr, L., Gelep, J. et al. Linoleic Acid Metabolite DiHOME Decreases Post-ischemic Cardiac Recovery in Murine Hearts. Cardiovasc Toxicol 19, 365–371 (2019). https://doi.org/10.1007/s12012-019-09508-x

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