Abstract 515: Inhibiting Dpp4 In Senescent Vascular Smooth Muscle Cells Suppresses A Coagulation Program

Abstract

In older persons, senescent vascular smooth muscle cells (VSMCs) express increased levels of senescence-associated secretory phenotype (SASP) factors such as cytokines, chemokines, adhesion molecules, matrix-remodeling enzymes, and angiogenic factors. The SASP contributes to destabilizing the plaque cap, suggesting that VSMC senescence promotes disease development. As a result of their prevalence in many diseases, major efforts are underway to develop therapies directed at senescent cells (senotherapies). 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 DPP4’s 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. Proteomic analysis of conditioned media from senescent hVSMCs treated with DPP4 inhibitors revealed a reduction in numerous complement and coagulation factors, indicating that DPP4 partially governs hemostasis and the proteolytic events that promote thrombotic signaling. We propose that DPP4 inhibition suppresses the pro-coagulation/complement phenotype of senescent hVSMCs to disrupt their function and improve vascular disease progression.