Analysis of vascular cell senescence to identify interventions in atherosclerosis

National Institute On Aging

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Abstract

The development of age-related multi-factorial diseases such as atherosclerosis is associated with persistent systemic inflammation. However, the interplay between aging, inflammation, and VSMC senescence is not well understood. Senescent cells exhibit a senescence-associated secretory phenotype (SASP) that includes the production of many proinflammatory cytokines (e.g., IL-6, IL-8, and IL-1), as well as chemokines (e.g., CCL2), adhesion molecules (e.g., ICAM-1), and angiogenic factors (e.g., VEGF). Recently, we have identified and published interesting a few candidates that regulate cell senescence and aging (Herman et. al., Nucleic Acid Res, 2021; Anerillas et al., Sci Adv, 2022; Tsitsipas et. al., Aging Cell, 2022) and published a review on lncRNAs (Herman et al., Mol Cell, 2022) and the epigenetic regulation of cardiovascular disease (Herman et al., J Cardiovascular Aging, 2021), both representing areas that may control processes key to cellular senescence and aging. One important protein is Dipeptidyl peptidase 4 (DPP4), which we found is highly expressed and active on the surface of senescent vascular cells. DPP4 expression is increased in mouse, monkey, and human atherosclerotic arteries, suggesting an important role in vascular disease. DPP4 also co-localizes with senescence-associated protein p16 in atherosclerotic aortas of old mice. Further, DPP4 silencing, or inhibition induces modest senescent cell death and suppresses a unique SASP produced by senescent VSMCs. Treatment of atherosclerotic mice with DPP4 inhibitor Vildagliptin reduced plaque necrotic core thickness and increased cap thickness, signifying increased plaque stability; however, we did not observe any change in plaque deposition. These results suggest DPP4-regulated factors may be more effective drug targets to reduce the burden of atherosclerosis by suppressing and removing senescent cells.