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Kynurenic acid, a key L-tryptophan-derived metabolite, protects the heart from an ischemic damage

Einat Bigelman, Metsada Pasmanik-Chor, Bareket Dassa, View ORCID ProfileMaxim Itkin, Sergey Malitsky, Orly Dorot, Edward Pichinuk, Smadar Levin-Zaidman, Nili Dezorella, Atan Gross, Anastasia Abashidze, Yuval Kleinberg, Gad Keren, Michal Entin-Meer
doi: https://doi.org/10.1101/2022.05.17.492275
Einat Bigelman
1Laboratory of Cardiovascular Research, Tel Aviv Sourasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Metsada Pasmanik-Chor
2Bioinformatics Unit, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Bareket Dassa
3Bioinformatics Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Maxim Itkin
4Metabolic Profiling Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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  • ORCID record for Maxim Itkin
Sergey Malitsky
4Metabolic Profiling Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Orly Dorot
5Bio-Imaging Core, Blavatnik Center for Drug Discovery, Tel-Aviv University, Tel-Aviv, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Edward Pichinuk
5Bio-Imaging Core, Blavatnik Center for Drug Discovery, Tel-Aviv University, Tel-Aviv, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Smadar Levin-Zaidman
6Electron microscopy unit, Weizmann Institute of Science, Rehovot, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Nili Dezorella
6Electron microscopy unit, Weizmann Institute of Science, Rehovot, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Atan Gross
7Faculty of Biology, Department of Biological Regulation, Department of Life Sciences, Weizmann Institute of Science, Rehovot, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Anastasia Abashidze
5Bio-Imaging Core, Blavatnik Center for Drug Discovery, Tel-Aviv University, Tel-Aviv, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Yuval Kleinberg
1Laboratory of Cardiovascular Research, Tel Aviv Sourasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Gad Keren
1Laboratory of Cardiovascular Research, Tel Aviv Sourasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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Michal Entin-Meer
1Laboratory of Cardiovascular Research, Tel Aviv Sourasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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  • For correspondence: michale@tlvmc.gov.il
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Abstract

Background Renal injury induces major changes in plasma and cardiac metabolites. We sought to identify a key metabolite that may affect cardiac mitochondria following an acute kidney injury (AKI) that may be harnessed to protect the heart following an acute ischemic event.

Methods and Results Metabolomics profiling of cardiac lysates and plasma samples derived from rats that underwent AKI 1 or 7 days earlier by 5/6 nephrectomy versus sham-operated controls was performed. We detected only 26 differential metabolites in both heart and plasma samples at the two selected time points, relative to sham. Out of which, kynurenic acid (kynurenate, KYNA) seemed most relevant. Interestingly, KYNA given at 10 mM concentration significantly rescued the viability of H9C2 cardiac myoblast cells grown under anoxic conditions and largely improved their mitochondrial structure and function as determined by flow cytometry and cell staining with MitoTracker dyes. Moreover, KYNA diluted in the drinking water of animals induced with an acute myocardial infarction, highly enhanced their cardiac recovery according to echocardiography and histopathology.

Conclusion and translational aspect KYNA may represent a key metabolite absorbed by the heart following AKI. This metabolite can enhance cardiac cell viability following an ischemic event in a mechanism that is mediated, at least in part, by the protection of the cardiac mitochondria. A short-term administration of KYNA may be highly beneficial in the treatment of the acute phase of kidney disease in order to attenuate progression to CRS and in ischemic cardiac conditions to reduce ischemic myocardial damage.

Highlights

  • The levels of the L-Tryptophan-derived metabolite, Kynurenic acid (KYNA), are significantly elevated in the heart and the plasma of animals induced with an acute kidney disease.

  • KYNA rescues the viability of cardiac cells from an ischemic damage both in vitro and in vivo.

  • KYNA can protect the structure & function of cardiac mitochondria in H9C2 cardiomyoblast cells upon exposure to anoxia.

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Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Funding: The work was supported by the TASMC-Weizmann collaborative grant (212843) and the Azrieli award foundation.

  • Conflict of interest: N/A

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 17, 2022.
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Kynurenic acid, a key L-tryptophan-derived metabolite, protects the heart from an ischemic damage
Einat Bigelman, Metsada Pasmanik-Chor, Bareket Dassa, Maxim Itkin, Sergey Malitsky, Orly Dorot, Edward Pichinuk, Smadar Levin-Zaidman, Nili Dezorella, Atan Gross, Anastasia Abashidze, Yuval Kleinberg, Gad Keren, Michal Entin-Meer
bioRxiv 2022.05.17.492275; doi: https://doi.org/10.1101/2022.05.17.492275
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Kynurenic acid, a key L-tryptophan-derived metabolite, protects the heart from an ischemic damage
Einat Bigelman, Metsada Pasmanik-Chor, Bareket Dassa, Maxim Itkin, Sergey Malitsky, Orly Dorot, Edward Pichinuk, Smadar Levin-Zaidman, Nili Dezorella, Atan Gross, Anastasia Abashidze, Yuval Kleinberg, Gad Keren, Michal Entin-Meer
bioRxiv 2022.05.17.492275; doi: https://doi.org/10.1101/2022.05.17.492275

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