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Premature senescence of human endothelial cells induced by inhibition of glutaminase

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Abstract

Cellular senescence is now recognized as an important mechanism of tumor suppression, and the accumulation of senescent cells may contribute to the aging of various human tissues. Alterations of the cellular energy metabolism are considered key events in tumorigenesis and are also known to play an important role for aging processes in lower eukaryotic model systems. In this study, we addressed senescence-associated changes in the energy metabolism of human endothelial cells, using the HUVEC model of in vitro senescence. We observed a drastic reduction in cellular ATP levels in senescent endothelial cells. Although consumption of glucose and production of lactate significantly increased in senescent cells, no correlation was found between both metabolite conversion rates, neither in young endothelial cells nor in the senescent cells, which indicates that glycolysis is not the main energy source in HUVEC. On the other hand, glutamine consumption was increased in senescent HUVEC and inhibition of glutaminolysis by DON, a specific inhibitor of glutaminase, led to a significant reduction in the proliferative capacity of both early passage and late passage cells. Moreover, inhibition of glutaminase activity induced a senescent-like phenotype in young HUVEC within two passages. Together, the data indicate that glutaminolysis is an important energy source in endothelial cells and that alterations in this pathway play a role in endothelial cell senescence.

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Abbreviations

ATP:

Adenosine triphosphate

DON:

6-diazo-5-oxo-l-norleucine

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HDF:

Human diploid fibroblasts

HUVEC:

Human umbilical vein endothelial cell

LDH:

Lactate dehydrogenase

PDL:

Population doubling

PK:

Pyruvate kinase

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Acknowledgements

We thank Bianca Kulik for excellent technical assistance. We thank Lutfan Lazuardi for help with statistical calculations. This work was supported by the Austrian Science Funds (FWF NRN S93), the European Union (CELLAGE project QLK6-CT-2001-00616) and the Austrian Ministry of Science and Traffic.

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Authors and Affiliations

  1. Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, Innsbruck, 6020, Austria

    Hermann Unterluggauer, Barbara Lener, Eveline Hütter, Werner Zwerschke & Pidder Jansen-Dürr

  2. Institute for Biochemistry and Endocrinology, Veterinary Faculty, University of Giessen, Frankfurter Strasse 100, 35392, Giessen, Germany

    Sybille Mazurek & Erich Eigenbrodt

  3. ScheBo Biotech AG, Netanyastrasse 3, 35394, Giessen, Germany

    Sybille Mazurek

  4. Tyrolean Cancer Research Institute, Innrain 66, Innsbruck, 6020, Austria

    Pidder Jansen-Dürr

Authors
  1. Hermann Unterluggauer
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  2. Sybille Mazurek
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  3. Barbara Lener
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  4. Eveline Hütter
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  5. Erich Eigenbrodt
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  6. Werner Zwerschke
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  7. Pidder Jansen-Dürr
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Correspondence to Pidder Jansen-Dürr.

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Prof. Dr. Erich Eigenbrodt deceased in 2004.

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Unterluggauer, H., Mazurek, S., Lener, B. et al. Premature senescence of human endothelial cells induced by inhibition of glutaminase. Biogerontology 9, 247–259 (2008). https://doi.org/10.1007/s10522-008-9134-x

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  • DOI: https://doi.org/10.1007/s10522-008-9134-x

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