Portal de Periódicos da CAPES

Impairing Senohemostasis by Ablating DPP4 Improves Atherosclerosis

2022; RELX Group (Netherlands); Linguagem: Inglês

10.2139/ssrn.4186256

1556-5068

Allison B. Herman, Dimitrios Tsitsipatis, Carlos Anerillas, Krystyna Mazan-Mamczarz, Angelica E. Carr, Jordan M. Gregg, Mingyi Wang, Jing Zhang, Marc Michel, 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 Demouth, Simone Sidoli, Luigi Ferrucci, Rafael de Cabo, Edward G. Lakatta, Myriam Gorospe,

Regulation of Appetite and Obesity

Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age as well as 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, and 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.Funding Information: This work was supported in part by the NIA IRP, NIH. The Sidoli lab gratefully acknowledges for financial support AFAR (Sagol Network GerOmics award), Deerfield (Xseed award), Relay Therapeutics, Merck, the NIH Office of the Director (1-S10- OD030286-01), the Einstein-Mount Sinai Diabetes Research Center, and the Einstein Cancer Center (P30-CA013330-47).Declaration of Interests: No conflicts of interest to report.Ethics Approval Statement: Segments of abdominal aortae were procured within 24-48 h of patients dying from non-cardiovascular deaths due to unnatural causes (homicide, suicide, or accident). This research activity is designated EXEMPT (NO 3353) by the Office of Human Subjects Research (OHSR) and has been entered in the OHSR database of the National Institutes of Health (NIH).All mouse work, including the import, housing, experimental procedures, and euthanasia, were done strictly under an Animal Study Proposal (ASP #474-LGG-2023) and associated amendments, reviewed and approved by the Animal Care and Use Committee (ACUC) of National Institute on Aging (NIA).