DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

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

doi:10.1172/JCI165933

DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

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 TanakaAnn Zenobia Moore, Megan E. DeMouth, Simone Sidoli, Luigi Ferrucci, Yie Liu, Rafael de Cabo, Edward G. Lakatta, Myriam Gorospe

Biochemistry

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Article number	e165933
Journal	Journal of Clinical Investigation
Volume	133
Issue number	12
DOIs	https://doi.org/10.1172/JCI165933
State	Published - Jun 15 2023

ASJC Scopus subject areas

General Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/JCI165933

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Herman, A. B., Tsitsipatis, D., Anerillas, C., Mazan-Mamczarz, K., Carr, A. E., Gregg, J. M., Wang, M., Zhang, J., Michel, M., Henry-Smith, C. A., Harris, S. C., Munk, R., Martindale, J. L., Piao, Y., Fan, J., Mattison, J. A., De, S., Abdelmohsen, K., Maul, R. W., ... Gorospe, M. (2023). DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice. Journal of Clinical Investigation, 133(12), Article e165933. https://doi.org/10.1172/JCI165933

Herman, AB, Tsitsipatis, D, Anerillas, C, Mazan-Mamczarz, K, Carr, AE, Gregg, JM, Wang, M, Zhang, J, Michel, M, Henry-Smith, CA, Harris, SC, Munk, R, Martindale, JL, Piao, Y, Fan, J, Mattison, JA, De, S, Abdelmohsen, K, Maul, RW, Tanaka, T, Moore, AZ, DeMouth, ME, Sidoli, S, Ferrucci, L, Liu, Y, de Cabo, R, Lakatta, EG & Gorospe, M 2023, 'DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice', Journal of Clinical Investigation, vol. 133, no. 12, e165933. https://doi.org/10.1172/JCI165933

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title = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, Herman et al.",

year = "2023",

month = jun,

day = "15",

doi = "10.1172/JCI165933",

language = "English (US)",

volume = "133",

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T1 - DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

AU - Herman, Allison B.

AU - Tsitsipatis, Dimitrios

AU - Anerillas, Carlos

AU - Mazan-Mamczarz, Krystyna

AU - Carr, Angelica E.

AU - Gregg, Jordan M.

AU - Wang, Mingyi

AU - Zhang, Jing

AU - Michel, Marc

AU - Henry-Smith, Charnae A.

AU - Harris, Sophia C.

AU - Munk, Rachel

AU - Martindale, Jennifer L.

AU - Piao, Yulan

AU - Fan, Jinshui

AU - Mattison, Julie A.

AU - De, Supriyo

AU - Abdelmohsen, Kotb

AU - Maul, Robert W.

AU - Tanaka, Toshiko

AU - Moore, Ann Zenobia

AU - DeMouth, Megan E.

AU - Sidoli, Simone

AU - Ferrucci, Luigi

AU - Liu, Yie

AU - de Cabo, Rafael

AU - Lakatta, Edward G.

AU - Gorospe, Myriam

PY - 2023/6/15

Y1 - 2023/6/15

N2 - 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.

AB - 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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JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 12

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DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

Abstract

ASJC Scopus subject areas

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