Calcitonin gene-related peptide inhibits angiotensin II-induced endothelial progenitor cells senescence through up-regulation of klotho expression

Background: It has been shown that angiotensin II (Ang II) is able to accelerate endothelial progenitor cells (EPCs) senescence through induction of oxidative stress. Calcitonin gene-related peptide (CGRP), a major neurotransmitter of the capsaicin-sensitive sensory nerves, protects endothelial function. Whether CGRP protects against EPCs senescence is unknown. Methods and results: In cord-derived EPCs, the effects of CGRP on Ang II-induced cell senescence were evaluated by exogenous application of CGRP and rutaecarpine (to stimulate the endogenous CGRP production) or by over-expression of CGRP. The anti-senescence mechanisms of CGRP on EPCs were investigated either by applying CGRP antagonist or by silence of klotho, an anti-aging protein. The results showed that both CGRP and klotho mRNA expression were reduced in Ang II-induced senescent EPCs. Exogenous application of CGRP inhibited Ang II-induced EPCs senescence by down-regulating the expression of NADPH oxidase and reactive oxygen species production. Similarly, rutaecarpine or CGRP I over-expression also inhibited Ang II-induced EPCs senescence. The effects of CGRP and rutaecarpine were reversed by CGRP(8-37), a select antagonist of CGRP receptor and capsazepine, a selective antagonist of transient receptor potential vanilloid 1, respectively. Furthermore, gene silence of klotho markedly attenuated the anti-senescence effect of CGRP on EPCs. Conclusions: The results suggest that CGRP can counteract Ang II-induced EPCs senescence through down-regulating the expression of NADPH oxidase and reactive oxygen species production and increasing the production of klotho. (C) 2010 Elsevier Ireland Ltd. All rights reserved.