Abstract P3124: Treatment Of Apoe -/- Mice With Advanced Atherosclerosis With The Senolytic Agent Abt-263 Caused Increased Mortality And Was Associated With Increased Endo-mt But Reduced Acta2 Cap Thickness And Collagen Content

Background: Plaque rupture and erosion of advanced atherosclerotic lesions resulting in ischemic heart disease or stroke are the leading worldwide cause of death. Multiple studies have shown that senescent cells are present in human atherosclerotic lesions, and recent animal studies have claimed that removing senescent cells from the lesions using senolytic agents has some beneficial effects but also limitations. Although these mouse studies have important implications for using senolytic agents to treat atherosclerosis, due to the lack of lineage tracing models and relying on markers not specific for various lesion cell types, it is difficult to ascertain the mechanisms that underline the beneficial effects shown by previous studies. Hypothesis: Treatment of western diet (WD) fed Apoe -/- mice with the senolytic agent ABT-263 (Navitoclax) will reduce lesion size and induce changes consistent with increased plaque stability including a thicker collagen-rich ACTA2 fibrous cap. Methods: SMC (Myh11-ERT2-Cre-eYFP+) and EC (Cdh5-ERT2-Cre-eYFP+) lineage tracing Apoe -/- were fed a WD for 18 weeks, followed by ABT-263 (100MG or 50MG /KG/BW) treatment for six to nine weeks on WD and analyzed for the indices of stability. Results: ABT-263 treatment did not result in changes in lesion size, lumen area, or outward remodeling of the brachiocephalic artery (BCA). However, surprisingly, ABT-263 treatment was associated with an 80% reduction in SMC (Myh11-eYFP+) but a 50-60% increase in endothelial cell (EC) contributions to lesions via EC to mesenchymal transition (EndoMT) (Chd5-eYFP+). ABT-263 treatment also reduced ACTA2 cap thickness by 50-75% and collagen content by 50%, but increased mortality by 50-60%. Conclusions: Taken together, contrary to our hypothesis, the senolytic agent ABT-263 treatment on advanced atherosclerosis showed multiple detrimental effects, including reduced indices of stability, increased Endo-MT, and increased mortality.