The angiotensin-(1-7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation
Author
Romero, Alejandra; San Hipólito-Luengo, Álvaro; Villalobos, Laura A.; Vallejo, Susana; Valencia, Inés; Michalska, Patrycja; Pajuelo-Lozano, Natalia; Sánchez Pérez, María Isabel; León, Rafael; Bartha Rasero, José Luis; Sanz, María Jesús; Erusalimsky, Jorge D.; Sánchez Ferrer, Carlos Félix; Romacho, Tania; Peiró Vallejo, M. ConcepciónEntity
UAM. Departamento de Bioquímica; UAM. Departamento de Farmacología; UAM. Departamento de Obstetricia y Ginecología; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)Publisher
Anatomical Society and John Wiley & Sons Ltd.Date
2019-06-01Citation
10.1111/acel.12913
Aging Cell 18.3 (2019): :e12913.
ISSN
1474-9718 (print); 1474-9726 (online)DOI
10.1111/acel.12913Funded by
Plan Nacional I+D+i, Grant/Award Number: SAF2017-84776-R, SAF2017-89714-R; Fundación La Caixa, Grant/Award Number: CaixaImpulse CI17/00048; IS Carlos III, Grant/Award Number: PI17/01700 and PI17/01401Project
Gobierno de España. SAF2017-84776-R; Gobierno de España. SAF2017-89714-R; Gobierno de España. PI17/01700; Gobierno de España. PI17/01401Editor's Version
https://doi.org/10.1111/acel.12913Subjects
Angiotensin-(1-7); Endothelial senescence; Heme oxygenase-1; Klotho; Nuclear factor (erythroid-derived 2)-like 2; Vascular aging; FarmaciaRights
© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley&Sons Ltd.Abstract
Endothelial cell senescence is a hallmark of vascular aging that predisposes to vascular disease. We aimed to explore the capacity of the renin–angiotensin system (RAS) heptapeptide angiotensin (Ang)-(1-7) to counteract human endothelial cell senescence and to identify intracellular pathways mediating its potential protective action. In human umbilical vein endothelial cell (HUVEC) cultures, Ang II promoted cell senescence, as revealed by the enhancement in senescence-associated galactosidase (SA-β-gal+) positive staining, total and telomeric DNA damage, adhesion molecule expression, and human mononuclear adhesion to HUVEC monolayers. By activating the G protein-coupled receptor Mas, Ang-(1-7) inhibited the pro-senescence action of Ang II, but also of a non-RAS stressor such as the cytokine IL-1β. Moreover, Ang-(1-7) enhanced endothelial klotho levels, while klotho silencing resulted in the loss of the anti-senescence action of the heptapeptide. Indeed, both Ang-(1-7) and recombinant klotho activated the cytoprotective Nrf2/heme oxygenase-1 (HO-1) pathway. The HO-1 inhibitor tin protoporphyrin IX prevented the anti-senescence action evoked by Ang-(1-7) or recombinant klotho. Overall, the present study identifies Ang-(1-7) as an anti-senescence peptide displaying its protective action beyond the RAS by consecutively activating klotho and Nrf2/HO-1. Ang-(1-7) mimetic drugs may thus prove useful to prevent endothelial cell senescence and its related vascular complications.
Files in this item
Google Scholar:Romero, Alejandra
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San Hipólito-Luengo, Álvaro
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Villalobos, Laura A.
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Vallejo, Susana
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Valencia, Inés
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Michalska, Patrycja
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Pajuelo-Lozano, Natalia
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Sánchez Pérez, María Isabel
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León, Rafael
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Bartha Rasero, José Luis
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Sanz, María Jesús
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Erusalimsky, Jorge D.
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Sánchez Ferrer, Carlos Félix
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Romacho, Tania
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Peiró Vallejo, M. Concepción
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