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.


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.
Zhou
Zhi
Z
Department of Pharmacology, School of Pharmaceutical Science, Central South University, Xiang-Ya Road 110#, Changsha 410078, Hunan, China.
Hu
Chang-Ping
CP
Wang
Chen-Jing
CJ
Li
Ting-Ting
TT
Peng
Jun
J
Li
Yuan-Jian
YJ
D000804:Angiotensin II / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000502:physiology*; D016922:Cellular Senescence; D042783:Endothelial Cells / Q000166:cytology*; D005312:Fetal Blood / Q000378:metabolism; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D019255:NADPH Oxidases / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D018384:Oxidative Stress; D034622:RNA Interference; D017382:Reactive Oxygen Species; D013234:Stem Cells / Q000166:cytology*; D015854:Up-Regulation
D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D019255:NADPH Oxidases; D005966:Glucuronidase; D000090265:Klotho Proteins; D015740:Calcitonin Gene-Related Peptide