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DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice
Allison B. Herman, … , Edward G. Lakatta, Myriam Gorospe
Allison B. Herman, … , Edward G. Lakatta, Myriam Gorospe
Published April 25, 2023
Citation Information: J Clin Invest. 2023;133(12):e165933. https://doi.org/10.1172/JCI165933.
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Research Article Aging Vascular biology Article has an altmetric score of 8

DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

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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.

Authors

Allison B. Herman, Dimitrios Tsitsipatis, Carlos Anerillas, Krystyna Mazan-Mamczarz, Angelica E. Carr, Jordan M. Gregg, Mingyi Wang, Jing Zhang, Marc Michel, Charnae’ A. Henry-Smith, Sophia C. Harris, Rachel Munk, Jennifer L. Martindale, Yulan Piao, Jinshui Fan, Julie A. Mattison, Supriyo De, Kotb Abdelmohsen, Robert W. Maul, Toshiko Tanaka, Ann Zenobia Moore, Megan E. DeMouth, Simone Sidoli, Luigi Ferrucci, Yie Liu, Rafael de Cabo, Edward G. Lakatta, Myriam Gorospe

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Figure 1

DPP4 is elevated and more active in senescent hVSMCs and mouse, monkey, and human atherosclerosis.

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DPP4 is elevated and more active in senescent hVSMCs and mouse, monkey, ...
(A) Schematic highlighting DPP4 function at the intersection of the senescence and atherosclerosis programs. (B) RT-qPCR analysis of the levels of DPP4, p21, and LMNB1 (Lamin B1) mRNAs in hVSMCs treated with DMSO, CoCl2 (200 nM), or Doxo (125 nM) for 7 days, normalized to ACTB (β-actin) mRNA levels. (C) hVSMCs were treated as in B, and the levels of proteins DPP4, p53, p21, and loading control ACTB were assessed by Western blot analysis. (D) Cell-surface proteins were biotinylated and pulled down in hVSMCs following treatment with DMSO, CoCl2, or Doxo for 7 days. Protein levels were assessed by Western blot analysis for cell-surface proteins DPP4 and VDAC1; VDAC1 input was included as a loading control. (E) DPP4 activity was measured in hVSMCs treated with DMSO, CoCl2, or Doxo for 7 days. (F) Western blot analysis of EGFR and RELA silencing in no treatment (NT) or Doxo-treated hVSMCs. (G) Ldlr–/– mice were fed ND or HFD for 16 weeks, and circulating DPP4 levels were measured in serum. (H) Aortas from 9 or 23 m.o. ApoE–/– mice were analyzed for p16 and DPP4. Original magnification, ×100. (I) Flow cytometry analysis of DPP4 on the surface of aortic VSMCs from young (n = 10) and old (n = 10) C57BL/6J mice. (J) RT-qPCR analysis of Cdkn1a, Cdkn2a, and Il1b mRNAs normalized to Actb mRNA from DPP4-positive or negative mouse VSMCs from young (n = 9, pooled 3 per data point) and old mice (n = 9, pooled 3 per data point) (Supplemental Figure 2A). (K) DPP4 in human aortic tissue (n = 5) was analyzed by IHC. Left: top row demonstrates DPP4 expression in plaque area; bottom row represents normal or nonplaque area of the same tissue. Right: analysis of the proportion of DPP4 in plaque and normal tissue in the total tissue area. Original magnification, ×10 (left panels); ×40 (right panels). (L) Immunofluorescent analysis of human atherosclerotic aortic media and neointima to colocalize DAPI (blue), DPP4 (purple), αSMA (orange), and p16 (green) signals. Original magnification, ×50 (left panels); ×100 (right panels). Data are represented as mean ± SD from n = 3 or otherwise indicated biological replicates. Significance was established using Student’s t test with Bonferroni’s correction. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001.

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