The role of rewired cysteine metabolism in vascular aging and regeneration.

• Applicant: Professorin Sofia Iris Bibli, Ph.D.
• Subject Area: Anatomy and Physiology ; Cardiology, Angiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449115771

Advanced age is the dominant unmodifiable risk factor for cardiovascular diseases. Several mechanisms have been proposed to contribute to the age-related changes in the vascular phenotype, however the majority of data have been derived from a combination of cell culture studies (using multi-passaged cells) and studies on rodents. There is a real lack of information on the aged human endothelium– largely because of the scarcity of access to native human endothelial cells from well phenotyped collectives. We have preliminary data from native mesenteric artery endothelial cells from young and aged human subjects that identifies cysteine catabolism as the most markedly impaired pathway in aged human endothelial cells. This is highly relevant given that the metabolism of cysteine to H2S results in the post-translational modification or S-sulfhydration of proteins involved in mechanosensing and redox balance as well as proteins that contribute to the anti-atherogenic properties of the endothelium. We also have evidence that H2S–independent effects of altered cysteinolysis contribute to metabolic and epigenetic mechanism that determine the regeneration capacity of the endothelium as well as endothelial-mesenchymal transition and aging. The work outlined in this proposal will address the hypothesis is that cysteinolysis driven by the enzyme cystathionine gamma lyase, determines endothelial cell fate by (i) modifying endothelial cell function through protein S-sulfhydration and tRNA thiolation, (ii) preserving endothelial bioenergetics, (iii) maintaining endothelial protein synthesis and (iv) affecting (hetero)chromatin dynamics. To assess the impact of cysteine catabolism on endothelial cell heterogeneity, plasticity and function during aging and vascular injury, we have designed a multidisciplinary study with in vitro, in vivo and in human studies coupled with omic approaches at a single cell level. The overall goal is to study the flux of cysteine-derived carbon and sulfur intermediates into metabolic pathways, proteomic alterations and chromatin homeostasis to determine whether a cause and defect relationship exists between cysteine metabolism and aging. In the process we aim to identify novel drugable approaches to improve the regenerative capacity of the aged endothelium.

• DFG Programme: Independent Junior Research Groups