Treatment of advanced atherosclerotic mice with the senolytic agent ABT-263 is associated with reduced indices of plaque stability and increased mortality

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.12.548696v1?rss=1 Authors: Karnewar, S., Karnewar, V., Shankman, L. S., Owens, G. K. Abstract: The use of senolytic agents to remove senescent cells from atherosclerotic lesions is controversial. A common limitation of previous studies is the failure to rigorously define the effects of senolytic agent ABT-263 (Navitoclax) on smooth muscle cells (SMC) despite studies claiming that they are the major source of senescent cells. Moreover, there are no studies of the effect of ABT-263 on endothelial cells (EC), which along with SMC comprise 90% of -SMA+ myofibroblast-like cells in the protective fibrous cap. Here we tested the hypothesis that treatment of advanced atherosclerotic mice with the ABT-263 will reduce lesion size and increase plaque stability. SMC (Myh11-CreERT2-eYFP) and EC (Cdh5-CreERT2-eYFP) lineage tracing Apoe-/- mice were fed a WD for 18 weeks, followed by ABT-263 100mg/kg/bw for six weeks or 50mg/kg/bw for nine weeks. ABT-263 treatment did not change lesion size or lumen area of the brachiocephalic artery (BCA). However, ABT-263 treatment reduced SMC by 90% and increased EC-contributions to lesions via EC-to-mesenchymal transition (EndoMT) by 60%. ABT-263 treatment also reduced -SMA+ fibrous cap thickness by 60% and increased mortality by greater than 50%. Contrary to expectations, treatment of WD-fed Apoe-/- mice with the senolytic agent ABT-263 resulted in multiple detrimental changes including reduced indices of stability, and increased mortality. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC