DPP4 Promotes human endothelial cell senescence and dysfunction via the PAR2–COX-2–TP axis and NLRP3 inflammasome activation
Author
Valencia Fernández, Inés; Vallejo Fernán, Susana; Dongil, Pilar; Romero, Alejandra; San Hipólito-Luengo, Álvaro; Shamoon, Licia; Posada, María; García Olmo, Damián; Carraro, Raffaelle; Erusalimsky, Jorge D.; Romacho Romero, Tania del Mar; Peiró Vallejo, M. Concepción; Sánchez Ferrer, Carlos FélixEntity
UAM. Departamento de CirugíaPublisher
American Heart AssociationDate
2022-07-01Citation
10.1161/HYPERTENSIONAHA.121.18477
Hypertension 79.7 (2022): 1361-1373
ISSN
1524-4563 (online); 0194-911X (print)DOI
10.1161/HYPERTENSIONAHA.121.18477Funded by
This work was supported by the Plan Nacional de I+D from the Spanish Ministry of Economy (grant numbers SAF2017-84776-R and PID2020-115590RB-100/AEI/10.13039/501100011033 to C.F. Sánchez-Ferrer and C. Peiró as coprincipal investigators), Boehringer Ingelheim España S.A., the Spanish Ministry of Education Formación de Profesorado Universitario, Ministerior de Educación y Cultura (FPU-MECD) program (grant number FPU16/02612 to I. Valencia), the Juan de la Cierva Incorporación contract (grant number IJCI-2015-24474 to T. Romacho), the European Social Fund and Comunidad Autónoma de Madrid program (grant numbers PEJ-2018-AI/SAL-9955 and PEJ-2017-AI/SAL-6867 to P. Dongil and A. Romero, respectively), and the Universidad Autónoma de Madrid Formación de Personal Investigador (FPI)-UAM program (grant numbers SFPI/2016-00981 and SFPI/2020-00053 to Á. San Hipólito-Luengo and L. Shamoon, respectively). The experiments performed with linagliptin were partly supported by Boehringer IngelheimProject
Gobierno de España. SAF2017-84776-REditor's Version
https://doi.org/10.1161/HYPERTENSIONAHA.121.18477Subjects
cellular senescence; dipeptidyl peptidase 4; endothelium; inflammasomes; microvessels; obesity; MedicinaRights
© 2022 American Heart Association, Inc.Abstract
Abnormal accumulation of senescent cells in the vessel wall leads to a compromised vascular function
contributing to vascular aging. Soluble DPP4 (dipeptidyl peptidase 4; sDPP4) secretion from visceral adipose tissue is enhanced in obesity, now considered a progeric condition. sDPP4 triggers vascular deleterious effects, albeit its contribution to vascular aging is unknown. We aimed to explore sDPP4 involvement in vascular aging, unraveling the molecular pathway by which sDPP4 acts on the endothelium. METHODS: Human endothelial cell senescence was assessed by senescence-associated β-galactosidase assay, visualization of DNA damage, and expression of prosenescent markers, whereas vascular function was evaluated by myography over human dissected microvessels. In visceral adipose tissue biopsies from a cohort of obese patients, we explored several agerelated parameters in vitro and ex vivo. RESULTS: By a common mechanism, sDPP4 triggers endothelial cell senescence and endothelial dysfunction in isolated human resistance arteries. sDPP4 activates the metabotropic receptor PAR2 (protease-activated receptor 2), COX-2 (cyclooxygenase 2) activity, and the production of TXA2 (thromboxane A2) acting over TP (thromboxane receptor) receptors (PAR2–COX2–TP axis), leading to NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing
3) inflammasome activation. Obese patients exhibited impaired microarterial functionality in comparison to control nonobese counterparts. Importantly, endothelial dysfunction in obese patients positively correlated with greater expression of DPP4, prosenescent, and proinflammatory markers in visceral adipose tissue nearby the resistance arteries. Moreover, when DPP4 activity or sDPP4-induced prosenescent mechanism was blocked, endothelial dysfunction was restored back to levels of healthy subjects. These results reveal sDPP4 as a relevant mediator in early vascular aging and highlight its capacity
activating main proinflammatory mediators in the endothelium that might be pharmacologically tackled
Files in this item
Google Scholar:Valencia Fernández, Inés
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Vallejo Fernán, Susana
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Dongil, Pilar
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Romero, Alejandra
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San Hipólito-Luengo, Álvaro
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Shamoon, Licia
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Posada, María
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García Olmo, Damián
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Carraro, Raffaelle
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Erusalimsky, Jorge D.
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Romacho Romero, Tania del Mar
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Peiró Vallejo, M. Concepción
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Sánchez Ferrer, Carlos Félix
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