Ketone body oxidation increases cardiac endothelial cell proliferation

Eva Maria Weis, Patrycja Puchalska, Alisa B Nelson, Jacqueline Taylor, Iris Moll, Sana S. Hasan, Matthias Dewenter, Marco Hagenmüller, Thomas Fleming, Gernot Poschet, Agnes Hotz-Wagenblatt, Johannes Backs, Peter Crawford, Andreas Fischer

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Blood vessel formation is dependent on metabolic adaption in endothelial cells. Glucose and fatty acids are essential substrates for ATP and biomass production; however, the metabolism of other substrates remains poorly understood. Ketone bodies are important nutrients for cardiomyocytes during starvation or consumption of carbohydrate-restrictive diets. This raises the question whether cardiac endothelial cells would not only transport ketone bodies but also consume some of these to achieve their metabolic needs. Here, we report that cardiac endothelial cells are able to oxidize ketone bodies and that this enhances cell proliferation, migration, and vessel sprouting. Mechanistically, this requires succinyl-CoA:3-oxoacid-CoA transferase, a key enzyme of ketone body oxidation. Targeted metabolite profiling revealed that carbon from ketone bodies got incorporated into tricarboxylic acid cycle intermediates as well as other metabolites fueling biomass production. Elevation of ketone body levels by a high-fat, low-carbohydrate ketogenic diet transiently increased endothelial cell proliferation in mouse hearts. Notably, in a mouse model of heart hypertrophy, ketogenic diet prevented blood vessel rarefication. This suggests a potential beneficial role of dietary intervention in heart diseases.

Original languageEnglish (US)
Article numbere14753
JournalEMBO Molecular Medicine
Volume14
Issue number4
DOIs
StatePublished - Apr 7 2022

Bibliographical note

Funding Information:
We thank Damir Krunic (DKFZ Light Microscopy Core Facility) for help with Fiji software data analysis and Cindy Körner (DKFZ Molecular Genome Analysis) for help with xCELLigence analysis, the Center for Preclinical Research, the Microarray Unit and High Throughput Sequencing Unit of the Genomics and Proteomics Core Facility and the Omics IT and Data Management (ODCF) of the German Cancer Research Center (DKFZ) for providing excellent services. This work was funded by the Deutsche Forschungsgemeinschaft (DFG) project no. 394046768 - SFB1366. Open Access funding enabled and organized by Projekt DEAL.

Funding Information:
We thank Damir Krunic (DKFZ Light Microscopy Core Facility) for help with Fiji software data analysis and Cindy Körner (DKFZ Molecular Genome Analysis) for help with xCELLigence analysis, the Center for Preclinical Research, the Microarray Unit and High Throughput Sequencing Unit of the Genomics and Proteomics Core Facility and the Omics IT and Data Management (ODCF) of the German Cancer Research Center (DKFZ) for providing excellent services. This work was funded by the Deutsche Forschungsgemeinschaft (DFG) project no. 394046768 ‐ SFB1366. Open Access funding enabled and organized by Projekt DEAL.

Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.

Keywords

  • angiogenesis
  • endothelial cell
  • heart
  • ketogenic diet
  • ketone bodies
  • Myocytes, Cardiac/metabolism
  • Animals
  • Cell Proliferation
  • Endothelial Cells/metabolism
  • Ketone Bodies/metabolism
  • Glucose/metabolism
  • Mice

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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