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

Santosh KarnewarVaishnavi KarnewarLaura S ShankmanGary K Owens
Published in: bioRxiv : the preprint server for biology (2023)
Treatment 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.
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