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A novel role for cystathionine γ lyase in the control of p53: impact on endothelial senescence and metabolic reprograming

Jiong Hu, Matthias S. Leisegang, Mario Looso, Gabrijela Dumbovic, Janina Wittig, Maria-Kyriaki Drekolia, Stefan Guenther, David John, Mauro Siragusa, Sven Zukunft, James Oo, Ilka Wittig, Susanne Hille, Andreas Weigert, Stefan Knapp, Ralf P. Brandes, Oliver J. Müller, Andreas Papapetropoulos, Fragiska Sigala, Gergana Dobreva, Ingrid Fleming, View ORCID ProfileSofia-Iris Bibli
doi: https://doi.org/10.1101/2022.09.05.506654
Jiong Hu
1Goethe University Frankfurt, Institute for Vascular Signalling, Centre for Molecular Medicine, Frankfurt am Main, Germany
2Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
PhD
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Matthias S. Leisegang
3Goethe University Frankfurt, Institute for Cardiovascular Physiology, Frankfurt am Main, Germany
PhD
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Mario Looso
4Bioinforatics Core Unit, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany
5German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany
PhD
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Gabrijela Dumbovic
6Goethe University Frankfurt, Institute of Cardiovascular Regeneration, Frankfurt am Main, Germany
PhD
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Janina Wittig
1Goethe University Frankfurt, Institute for Vascular Signalling, Centre for Molecular Medicine, Frankfurt am Main, Germany
MSc
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Maria-Kyriaki Drekolia
1Goethe University Frankfurt, Institute for Vascular Signalling, Centre for Molecular Medicine, Frankfurt am Main, Germany
MSc
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Stefan Guenther
4Bioinforatics Core Unit, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany
5German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany
PhD
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David John
6Goethe University Frankfurt, Institute of Cardiovascular Regeneration, Frankfurt am Main, Germany
PhD
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Mauro Siragusa
1Goethe University Frankfurt, Institute for Vascular Signalling, Centre for Molecular Medicine, Frankfurt am Main, Germany
PhD
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Sven Zukunft
1Goethe University Frankfurt, Institute for Vascular Signalling, Centre for Molecular Medicine, Frankfurt am Main, Germany
PhD
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James Oo
3Goethe University Frankfurt, Institute for Cardiovascular Physiology, Frankfurt am Main, Germany
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Ilka Wittig
7Goethe University Frankfurt, Functional Proteomics, Institute for Cardiovascular Physiology, Frankfurt am Main, Germany
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Susanne Hille
8Department of Internal Medicine III, University of Kiel, Kiel, Germany
MSc
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Andreas Weigert
9Goethe University Frankfurt, Institute of Biochemistry I, Frankfurt am Main, Germany
PhD
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Stefan Knapp
10Goethe University Frankfurt, Institute for Pharmaceutical Chemistry and Buchmann Institute for Molecular Life Sciences, Frankfurt am Main, Germany
PhD
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Ralf P. Brandes
3Goethe University Frankfurt, Institute for Cardiovascular Physiology, Frankfurt am Main, Germany
5German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany
MD
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Oliver J. Müller
8Department of Internal Medicine III, University of Kiel, Kiel, Germany
11German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Kiel, Germany
MD
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Andreas Papapetropoulos
12Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
13Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
PhD
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Fragiska Sigala
14First Propedeutic Department of Surgery, Vascular Surgery Division, National and Kapodistrian University of Athens Medical School, Athens, Greece
MD
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Gergana Dobreva
15Cardiovascular Genomics and Epigenomics, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
16German Centre for Cardiovascular Research (DZHK), partner site Heidelberg, Heidelberg, Germany
PhD
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Ingrid Fleming
1Goethe University Frankfurt, Institute for Vascular Signalling, Centre for Molecular Medicine, Frankfurt am Main, Germany
5German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany
PhD
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  • For correspondence: bibli@vrc.uni-frankfurt.de fleming@em.uni-frankfurt.de
Sofia-Iris Bibli
1Goethe University Frankfurt, Institute for Vascular Signalling, Centre for Molecular Medicine, Frankfurt am Main, Germany
5German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany
PhD
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  • ORCID record for Sofia-Iris Bibli
  • For correspondence: bibli@vrc.uni-frankfurt.de fleming@em.uni-frankfurt.de
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Abstract

Aims Advanced age is unequivocally linked to the development of cardiovascular disease, however, the mechanisms leading to loss of endothelial cell regenerative capacity during aging remain poorly understood. Here we aimed to investigate novel mechanisms involved in endothelial cell senescence, that impact on endothelial cell transcription and the vascular repair response upon injury

Methods and results RNA sequencing of a unique collection of native endothelial cells from young and aged individuals, showed that aging (20 vs. 80 years) is characterized by p53- mediated reprogramming to promote the expression of senescence-associate genes. Molecular analysis revelead that p53 accumulated and acetylated in the nucleus of aged human endothelial cells to suppress glycolysis. Metabolic flux analysis identified an associated reduction in glucose uptake and ATP availability that inhibited the assembly of the telomerase complex, which was essential for proliferation. Nuclear translocation of p53 in aged endothelial cells was attributed to the loss of the vasoprotective enzyme, cystathionine γ-lyase (CSE), which physically anchored p53 in the cytosol. In mice, loss of endothelial cell CSE activated p53 and arrested vascular repair upon injury, while the AAV9 mediated re-expression of an active CSE mutant retained p53 in the cytosol, maintained endothelial glucose metabolism and proliferation, and prevented endothelial cell senescence. Adenoviral overexpression of CSE in human native aged endothelial cells maintained low p53 activity and re-activated telomerase to revert endothelial cell senescence.

Conclusion Our data identified the interaction between CSE and p53 as a promising target to preserve vascular regeneration during aging.

Key Question To identify the mechanisms that regulate endothelial cell senescence under native conditions and their impact on vascular repair in aging.

Key Finding Lack of a physical interaction between CSE and p53 metabolically reprogrammes endothelial cells to reduce telomerase activity and halt endothelial cell regeneration.

Take home message Interventions to increase CSE expression represent a novel therapy against p53-induced endothelial cell cycle arrest and senescense

Translational perspective Endothelial rejuvenation strategies could serve as promising therapies against age-related cardiovascular diseases. By investigating human native endothelial cells from young and aged individuals, we identified that the age-related nuclear accumulation of p53 reprograms endothelial cell metabolism, regulates telomerase activity and inhibits endothelial cell regeneration. Nuclear localization of p53 resulted from a loss of its interaction with the cysteine catabolizing enzyme cystathionine γ-lyase in the cytoplasm. Enhancing the physical interaction of p53 with CSE by gene therapy could revert endothelial cell senescence and activate endothelial reparative responses.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵# First author: Jiong Hu, PhD

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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A novel role for cystathionine γ lyase in the control of p53: impact on endothelial senescence and metabolic reprograming
Jiong Hu, Matthias S. Leisegang, Mario Looso, Gabrijela Dumbovic, Janina Wittig, Maria-Kyriaki Drekolia, Stefan Guenther, David John, Mauro Siragusa, Sven Zukunft, James Oo, Ilka Wittig, Susanne Hille, Andreas Weigert, Stefan Knapp, Ralf P. Brandes, Oliver J. Müller, Andreas Papapetropoulos, Fragiska Sigala, Gergana Dobreva, Ingrid Fleming, Sofia-Iris Bibli
bioRxiv 2022.09.05.506654; doi: https://doi.org/10.1101/2022.09.05.506654
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A novel role for cystathionine γ lyase in the control of p53: impact on endothelial senescence and metabolic reprograming
Jiong Hu, Matthias S. Leisegang, Mario Looso, Gabrijela Dumbovic, Janina Wittig, Maria-Kyriaki Drekolia, Stefan Guenther, David John, Mauro Siragusa, Sven Zukunft, James Oo, Ilka Wittig, Susanne Hille, Andreas Weigert, Stefan Knapp, Ralf P. Brandes, Oliver J. Müller, Andreas Papapetropoulos, Fragiska Sigala, Gergana Dobreva, Ingrid Fleming, Sofia-Iris Bibli
bioRxiv 2022.09.05.506654; doi: https://doi.org/10.1101/2022.09.05.506654

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