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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Vydané v:	The Journal of clinical investigation Ročník 133; číslo 12; s. 1 - 18
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States American Society for Clinical Investigation 15.06.2023
Predmet:	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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI165933