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ResearchIn-Press PreviewAgingVascular biology Open Access | 10.1172/JCI165933

DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

Allison B. Herman,1 Dimitrios Tsitsipatis,1 Carlos Anerillas,1 Krystyna Mazan-Mamczarz,1 Angelica E. Carr,3 Jordan M. Gregg,1 Mingyi Wang,4 Jing Zhang,4 Marc Michel,1 Charnae' Henry-Smith,1 Sophia C. Harris,4 Rachel Munk,1 Jennifer L Martindale,1 Yulan Piao,1 Jinshui Fan,1 Julie A. Mattison,5 Supriyo De,1 Kotb Abdelmohsen,1 Robert W. Maul,6 Toshiko Tanaka,5 Ann Z. Moore,5 Megan E. DeMouth,7 Simone Sidoli,8 Luigi Ferrucci,5 Yie Liu,1 Rafael de Cabo,5 Edward G. Lakatta,4 and Myriam Gorospe1

1Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

2Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Blatimore, United States of America

3Laboratory of Genetics and Genomic, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

4Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

5Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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2Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Blatimore, United States of America

3Laboratory of Genetics and Genomic, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

4Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

5Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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2Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Blatimore, United States of America

3Laboratory of Genetics and Genomic, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

4Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

5Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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2Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Blatimore, United States of America

3Laboratory of Genetics and Genomic, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

4Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

5Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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3Laboratory of Genetics and Genomic, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

4Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

5Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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4Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

5Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

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8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

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6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

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6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

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8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

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6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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5Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, United States of America

7Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States of America

8Department of Biochemistry, Albert Einstein College of Medcine, Bronx, United States of America

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Published April 25, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI165933.
Copyright © 2023, Herman et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 25, 2023 - Version history
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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.

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graphical abstract
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