DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

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 V...

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Published in:The Journal of clinical investigation Vol. 133; no. 12; pp. 1 - 18
Main Authors: Herman, Allison B., Tsitsipatis, Dimitrios, Anerillas, Carlos, Mazan-Mamczarz, Krystyna, Carr, Angelica E., Gregg, Jordan M., Wang, Mingyi, Zhang, Jing, Michel, Marc, Henry-Smith, Charnae’ A., Harris, Sophia C., Munk, Rachel, Martindale, Jennifer L., Piao, Yulan, Fan, Jinshui, Mattison, Julie A., De, Supriyo, Abdelmohsen, Kotb, Maul, Robert W., Tanaka, Toshiko, Moore, Ann Zenobia, DeMouth, Megan E., Sidoli, Simone, Ferrucci, Luigi, Liu, Yie, de Cabo, Rafael, Lakatta, Edward G., Gorospe, Myriam
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 15.06.2023
Subjects:
Aging
Arteriosclerosis
Atherosclerosis
Biomedical research
Blood circulation disorders
Cardiovascular diseases
Care and treatment
Cell cycle
Cell death
Cells
Coagulation factors
Development and progression
Diabetes
Disease
Disease susceptibility
Fibroblasts
Genotype & phenotype
Health aspects
Hemostasis
Hypoxia
Inflammation
Kinases
Muscle cells
Phenotypes
Protease inhibitors
Proteins
Scientific equipment and supplies industry
Senescence
Serine proteinase
Smooth muscle
Testing
Thrombin
Type 2 diabetes
Vascular biology
Vascular diseases
Vascular smooth muscle
United States
Maryland
Aging
Vascular Biology
Atherosclerosis
Cellular senescence
ISSN:1558-8238, 0021-9738, 1558-8238
Online Access:Get full text
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Summary: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.
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ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI165933