The angiotensin-(1-7)/Mas receptor a xis protects from endothelial cell senescence via klotho and Nrf2 activation
Hipólito-Luengo, Álvaro San
Bartha, José Luis
Sanz, María J.
Sánchez-Ferrer, Carlos F.
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Endothelial cell senescence is a hallmark of va scular aging that pre disposes 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 mediati ng its potential protective action. In human umbilical vein endothelial cell (HUVEC) cult ures, Ang II promoted cell senescence, as revealed by the enhancement in se nescence-associated galactosidase (SA- -gal+) positive staining, total and telomeric DNA damage, adhesion molecules expression and human mononuclear adhesion to HUVEC monolaye rs. By activating the G-coupled receptor Mas, Ang-(1-7) inhibit ed the pro-senescence action of Ang II, but also of a non- RAS stressor such as the cytokine IL-1 . Moreover, Ang-(1-7) enhanced endothelial klotho levels, while klotho silencing resulted in th e 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 ide ntifies Ang-(1-7) as an anti-senescence peptide displaying its protectiv e action beyond the RAS by consecutively activating klotho and Nrf2/HO-1. Ang-(1-7) mimetic dru gs may thus prove useful to prevent endothelial cell senescence and its re lated vascular complications.
Romero, A., San Hipólito‐Luengo, Á., Villalobos, L.A., Vallejo, S., Valencia, I., Michalska, P., Pajuelo‐Lozano, N., Sánchez‐Pérez, I., León, R., Bartha, J.L. and Sanz, M.J. (2019) 'The angiotensin‐(1‐7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation', Aging Cell, p.e12913. DOI: 10.1111/acel.12913.
Article published in Aging Cell on 17 February 2019 (online), available open access at: https://doi.org/10.1111/acel.12913.
Cardiff Metropolitan University (Grant ID: Cardiff Metropolian (Internal))
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