Analysis of vascular cell senescence to identify interventions in atherosclerosis

National Institute On Aging

Investigators

Linked publications, trials & patents

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., Nature Communications, 2022; Tsitsipatis et. al., Aging Cell, 2022; Rossi et al., Elife, 2023) 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. Dipeptidyl Peptidase 4 (DPP4), a serine protease, was elevated on the plasma membrane of senescent fibroblasts. While the effect of DPP4 on VSMCs is not well understood, DPP4 inhibitors such as Vildagliptin are clinically used to treat diabetes, and in animal models, gliptins reduced atherosclerosis and inflammation independently of DPP4s canonical role in glucose metabolism. We hypothesized that DPP4 inhibitors may reduce the progression and burden of atherosclerosis by preventing DPP4 enzymatic function on senescent VSMCs. Towards this end, we discovered that DPP4 protein levels and enzymatic activity increased in senescent human VSMCs (hVSMCs) senescence. We also found elevated DPP4 in human atherosclerotic plaques, and high levels of DPP4 colocalized with the senescence marker p16 in murine atherosclerosis. Strikingly, silencing DPP4 in senescent hVSMCs increased cell death and caspase activity. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated secretory phenotype (SASP) signature comprising many complement and coagulation factors; the levels of these factors declined following DPP4 inhibition. In human serum samples with high and low Framingham risk scores, a measure of cardiovascular risk, these proteins related to complement and coagulation were increased. Further, DPP4 inhibition reduced senescent cell burden and coagulation in atherosclerotic mice, suggesting that downstream factors affected by DPP4 activity may be promising therapeutic targets in vascular diseases. Lastly, single-cell resolution of senescent VSMCs validated the senohemostatic properties of DPP4i in murine atherosclerosis. The results from this study provide a new area of investigation to reduce or suppress senescent vascular cell function to improve the burden of atherosclerosis by senohemostasis (Herman et al., Journal of Clinical Investigation, 2023).