The Role of Cellular Senescence in Atherosclerosis

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 DESCRIPTION (provided by applicant): Atherosclerosis is one of the most common age-related causes of morbidity and mortality. The underlying causes of the progression from clinically-silent, benign disease to rupture-prone vulnerable plaques are incompletely understood, but include plaque destabilizing protease and inflammatory factor production. One potential source of these factors is the secretome of senescent cells, which have been hypothesized to accumulate in plaques based on senescence-associated β-galactosidase staining of lesions. The role of senescent cells in atherogenesis remained unclear without the availability of transgenic tools to selectively remove these cells. To address this technical defict, in preliminary studies we demonstrated that drug- inducible killing of senescent cells using the 3MR transgene resulted in reduced plaque size and number. This observation, in addition to overlap between pro-atherogenic factors and components of the senescent secretome, led to the central hypothesis that senescent cells drive atherogenesis and plaque destabilization via their pro-inflammatory, proteolytic secretome. To test this hypothesis, we will pursue three aims. In the first aim, we will identify the stage of atherosclerosis at which senescence occurs and which cells become senescent. In the second aim, we will identify the mechanisms by which these cells become senescent and how they promote plaque formation. In the third aim, we will test whether senescent cell killing promotes beneficial remodeling or regression of established plaques. The long-term goal of our research is to target senescent cells for killing as a novel therapy for age-related diseases, such as atherosclerosis. The overall impact of this project is that it will increase our knowledge of basic atherosclerosis biology and integrate cellular senescence into our models of this disease. Further, completion of this research may justify targeting senescent cells as a therapeutic intervention in cardiovascular disease.