Targeting lipids to regulate endothelial cell senescence

Abstract

Endothelial cell senescence, marked by irreversible growth arrest, is a major factor in vascular aging and cardiovascular disease, such as atherosclerosis. One of the key drivers of senescence is oxidative stress, which leads to the activation of various signalling pathways involved in senescence progression, including p53/p21WAF1/CIP1 and p16INK4A/Rb pathways. Hydrogen peroxide (H2O2) is commonly used to achieve oxidative stress-induced premature senescence in vitro. Despite progress, the exact molecular mechanisms and regulatory factors governing this process are not fully understood.

Sphingolipids have drawn attention due to their potential role in controlling endothelial cell senescence. These diverse membrane-constituting and bioactive lipids regulate various cellular processes, including cell survival, proliferation, and inflammation. Disruption in sphingolipid metabolism and signalling have been implicated in the development of age-related diseases. Hence, understanding sphingolipid's role in endothelial cell senescence is crucial for unravelling cardiovascular disorders.

In this thesis, I aim to investigate the key sphingolipids that dictate premature senescence in endothelial cells induced by H2O2. To assess this, I employed several sphingolipid compounds and their metabolic enzyme inhibitors to alter the levels of certain sphingolipid species. I found increasing sphingosine levels by the addition of exogenous sphingosine or inhibition of its catabolic enzyme sphingosine kinase 1 drove the establishment of endothelial cell senescence. Conversely, reducing sphingosine levels by inhibition of ceramide synthase or acid ceramidase inhibited H2O2-induced endothelial cell senescence.

This thesis identified sphingosine, but not ceramide or sphingosine 1-phosphate, as the key determinant of endothelial cell senescence, paving the way for future research into the molecular mechanisms and guiding the development of sphingosine-targeted senolytic therapeutics.