DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

Abstract

Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage, and secrete factors that promote atherosclerotic plaque vulnerability and disease.Here, we report increased levels and activity of dipeptidyl peptidase 4 (DPP4), a serine protease, in senescent VSMCs. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated secretory phenotype (SASP) signature comprising many complement and coagulation factors; silencing or inhibiting DPP4 reduced these factors and increased cell death. Serum samples from persons with high risk for cardiovascular disease contained high levels of DPP4-regulated complement and coagulation factors. Importantly, DPP4 inhibition reduced senescent cell burden and coagulation and improved plaque stability, while single-cell resolution of senescent VSMCs reflected the senomorphic and senolytic effects of DPP4 inhibition in murine atherosclerosis. We propose that DPP4-regulated factors could be exploited therapeutically to reduce senescent cell function, reverse senohemostasis, and improve vascular disease. Herman et al.,3

Sitagliptin Extends Lifespan of Caenorhabditis elegans by Inhibiting Insulin/Insulin-Like Signaling and Activating Dietary Restriction-Like Signaling Pathways

“…Furthermore, recent research has shown that DPP-4 inhibitors possess senomorphic properties by reducing the senescence-associated secretory phenotype of senescent human vascular smooth muscle cells [55]. Additionally, DPP-4 has been identified as a cell surface marker associated with senescence-associated secretory phenotype characteristics [56], further supporting the notion that DPP-4 inhibitors like SIT likely function as senomorphics rather than senolytics.…”

TMT-Based Proteomics Analysis of Senescent Nucleus Pulposus from Patients with Intervertebral Disc Degeneration

“…Recent studies have indicated that IDD is a complex cell-mediated disease that involves NP cell senescence [4,[7][8][9]. NP senescence is characterized by increased expression of p16 INK4A and p21 CIP proteins, and secretion of bioactive molecules such as MMP3, MMP13, interleukin (IL)-6, and IL-8; this is known as the senescence-associated secretory phenotype (SASP) [10][11][12][13]. SASP accelerates senescence in neighboring cells and causes intervertebral disc dysfunction and structural deterioration.…”

Dipeptidyl peptidase‐4 inhibition targeting vascular senescence as a novel treatment for atherosclerosis

“…In the article by Herman et al 1 ,. the importance of dipeptidyl peptidase‐4 (DPP4) in senescent vascular smooth muscle cells (VSMCs) and atherosclerosis is highlighted.…”

“…In the article by Herman et al . 1 , the importance of dipeptidyl peptidase‐4 (DPP4) in senescent vascular smooth muscle cells (VSMCs) and atherosclerosis is highlighted. In senescent VSMCs, the expression of DPP4 was higher and correlated with enhanced expression of senescence‐associated secretory phenotype (SASP) factors, especially several complement and coagulation factors.…”

“…Several agents have been proposed as having clinical potential for senolysis or senomorphic effects in atherosclerosis. In this article, DPP4 inhibition is first proposed as a senotherapy 1 . The study showed that there is an elevation in both the amount of surface DPP4 and the expression level of DPP4 messenger ribonucleic acid in senescent VSMCs.…”