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

Abstract

AbstractThe 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 α-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 tracingApoe-/-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 α-SMA+fibrous cap thickness by 60% and increased mortality by >50%. Contrary to expectations, treatment of WD-fedApoe-/-mice with the senolytic agent ABT-263 resulted in multiple detrimental changes including reduced indices of stability, and increased mortality.Graphical abstractUploaded separately.HighlightsTreatment of Apoe-/- mice with advanced atherosclerosis with the senolytic agent ABT-263 increased mortality by >50%.ABT-263 showed a 90% reduction in SMC but a 60% increase in endothelial cell (EC) contributions to lesions via EC to mesenchymal transition (EndoMT) but prevented adaptive increases in investment of EC-derived cells into the fibrous cap via beneficial EndoMT to myofibroblast transitions that we have shown normally occur when SMC investment into fibrous cap of lesions is impaired.Knock out (KO) of Klf4 in SMC, which results in smaller but more stable atherosclerotic lesions, was associated with reduced expression of pro-senescence markers, but preserved expression of the anti-senescence marker, telomerase reverse transcriptase although it is unclear if the latter is causal or an effect.