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

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 >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. Graphical abstractUploaded separately. O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/548696v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@2ca235org.highwire.dtl.DTLVardef@4d864aorg.highwire.dtl.DTLVardef@1ab76e4org.highwire.dtl.DTLVardef@aa2c7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LITreatment of Apoe-/- mice with advanced atherosclerosis with the senolytic agent ABT-263 increased mortality by >50%. C_LIO_LIABT-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. C_LIO_LIKnock 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. C_LI