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

Hu, J.; Leisegang, M. S.; Looso, M.; Dumbovic, G.; Wittig, J.; Drekolia, M.-K.; Guenther, S.; John, D.; Siragusa, M.; Zukunft, S.; Oo, J.; Wittig, I.; Hille, S.; Weigert, A.; Knapp, S.; Brandes, R. P.; Mueller, O. J.; Papapetropoulos, A.; Sigala, F.; Dobreva, G.; Fleming, I.; Bibli, S. I.

doi:10.1101/2022.09.05.506654

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bioRxiv · 10.1101/2022.09.05.506654

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

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Abstract

AimsAdvanced 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 resultsRNA 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 {gamma}-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. ConclusionOur data identified the interaction between CSE and p53 as a promising target to preserve vascular regeneration during aging. Key QuestionTo identify the mechanisms that regulate endothelial cell senescence under native conditions and their impact on vascular repair in aging. Key FindingLack of a physical interaction between CSE and p53 metabolically reprogrammes endothelial cells to reduce telomerase activity and halt endothelial cell regeneration. Take home messageInterventions to increase CSE expression represent a novel therapy against p53-induced endothelial cell cycle arrest and senescense Translational perspectiveEndothelial 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 {gamma}-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.

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Hu, J., Leisegang, M. S., Looso, M., Dumbovic, G., Wittig, J., Drekolia, M.-K., Guenther, S., John, D., Siragusa, M., Zukunft, S., Oo, J., Wittig, I., Hille, S., Weigert, A., Knapp, S., Brandes, R. P., Mueller, O. J., Papapetropoulos, A., Sigala, F., Dobreva, G., Fleming, I., Bibli, S. I.. 2022-09-05. A novel role for cystathionine gamma lyase in the control of p53: impact on endothelial senescence and metabolic reprograming. https://doi.org/10.1101/2022.09.05.506654

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