The angiotensin‐(1‐7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation

• Published in: Aging cell Vol. 18; no. 3; pp. e12913 - n/a
• Main Authors: Romero, Alejandra, San Hipólito‐Luengo, Álvaro, Villalobos, Laura A., Vallejo, Susana, Valencia, Inés, Michalska, Patrycja, Pajuelo‐Lozano, Natalia, Sánchez‐Pérez, Isabel, León, Rafael, Bartha, José Luis, Sanz, María Jesús, Erusalimsky, Jorge D., Sánchez‐Ferrer, Carlos F., Romacho, Tania, Peiró, Concepción
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2019; John Wiley and Sons Inc
• Subjects: Aging; Angiotensin; Angiotensin I - pharmacology; Angiotensin II; angiotensin‐(1‐7); Blood circulation disorders; Cell activation; Cells, Cultured; Cellular Senescence - drug effects; DNA damage; Endothelial cells; endothelial senescence; Endothelium; G proteins; Glucuronidase - metabolism; Heme; heme oxygenase‐1; Human Umbilical Vein Endothelial Cells - metabolism; Humans; klotho; Klotho protein; NF-E2-Related Factor 2 - metabolism; nuclear factor (erythroid‐derived 2)‐like 2; Original Paper; Original Papers; Oxygenase; Peptide Fragments - pharmacology; Protoporphyrin; Protoporphyrin IX; Receptors, G-Protein-Coupled - metabolism; Renin; Senescence; Tin protoporphyrin; Umbilical vein; vascular aging; Vascular diseases; endothelial senescence; klotho; angiotensin-(1-7); heme oxygenase-1; nuclear factor (erythroid-derived 2)-like 2; vascular aging
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12913

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.