Alejandra Romero1, Álvaro San Hipólito‐Luengo1, Laura A. Villalobos1, Susana Vallejo1,2, Inés Valencia1, Patrycja Michalska1,3, Natalia Pajuelo‐Lozano4,5, Isabel Sánchez‐Pérez6,4,5, Rafael León3,7, José Luis Bartha8,2, María‐Jesús Sanz9,10, Jorge D. Erusalimsky11, Carlos F. Sánchez‐Ferrer1,2, Tania Romacho1, Concepción Peiró1,2
1Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
2Instituto de Investigaciones Sanitarias (IdiPAZ), Madrid, Spain
3Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
4Department of Biochemistry Faculty of Medicine Universidad Autónoma de Madrid Madrid Spain
5Instituto de Investigaciones Biomédicas UAM-CSIC Madrid Spain
6CIBER for Rare Diseases Valencia Spain
7Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain
8Department of Obstetrics and Gynecology Faculty of Medicine Universidad Autónoma de Madrid Madrid Spain
9Department of Pharmacology, Universidad de Valencia, Valencia, Spain
10Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain
11School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
Tóm tắt
AbstractEndothelial 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.
