Effects of estrogen on stress-induced premature senescence of vascular smooth muscle cells: A novel mechanism for the "time window theory" of menopausal hormone therapy

Zhu, Congli, Zhang, Liang, Zheng, Yong, Xu, Jing, Song, Jian, Rolfe, Barbara E. and Campbell, Julie H. (2011) Effects of estrogen on stress-induced premature senescence of vascular smooth muscle cells: A novel mechanism for the "time window theory" of menopausal hormone therapy. Atherosclerosis, 215 2: 294-300. doi:10.1016/j.atherosclerosis.2010.12.025


Author Zhu, Congli
Zhang, Liang
Zheng, Yong
Xu, Jing
Song, Jian
Rolfe, Barbara E.
Campbell, Julie H.
Title Effects of estrogen on stress-induced premature senescence of vascular smooth muscle cells: A novel mechanism for the "time window theory" of menopausal hormone therapy
Journal name Atherosclerosis   Check publisher's open access policy
ISSN 0021-9150
1879-1484
Publication date 2011-04
Sub-type Article (original research)
DOI 10.1016/j.atherosclerosis.2010.12.025
Volume 215
Issue 2
Start page 294
End page 300
Total pages 7
Place of publication Brookvale Plaza, E. Park, Shannon, Co. Clare, Ireland
Publisher Elsevier Ireland
Collection year 2012
Language eng
Formatted abstract
Objectives: To investigate the effects of estrogen on stress-induced premature senescence of vascular smooth muscle cells (VSMCs) and the underlying mechanisms.

Methods: VSMCs of passage 2-3 cultured from young (2 months) and old (18 months) female SD rats were induced into premature senescence by exposure to 150μmol/L H2O2 in the presence or absence of different concentrations of 17β-estradiol (E2). The expression or activation of senescence-associated beta-galactosidase (SA-β-Gal), DcR2, oncogene Ras, p38, PRAK, p53, p21, p16 and Rb was detected by flow cytometry, pull-down assay or Western blot.

Results: Flow cytometry analysis showed that in the VSMCs from young rats pre-administration of E2 significantly suppressed the H2O2-induced premature senescence (reducing both percentage of SA-β-Gal positive cells and cellular expression of DcR2) in a dose-dependent manner; these senescent-inhibiting effects of E2 could be blocked by an estrogen receptor antagonist ICI 182,780 (10-5mol/L). Pull-down assay or Western blot analysis revealed that pre-administration of 10-8mol/L E2 significantly reduced the H2O2-induced activation of oncogene Ras, as well as activity of p16 and p38 MAPK, and expression of PRAK, p53, p21and p-Rb. Unexpectedly, in the VSMCs from old rats the senescent-inhibiting effect of E2 disappeared and switched to a senescent-promoting action at 10-8mol/L. This senescent-promoting effect could be enhanced by ICI 182,780 and eliminated by a cytochrome P450s inhibitor ABT.

Conclusion: Estrogen inhibits stress-induced premature senescence of VSMCs from young female through its receptor-mediated surpression of both Ras-p38-PRAK-p53-p21-Rb and Ras-p16-Rb pathways, but this effect disappeared and even more switched to a senescent-promoting action in the cells from old body probably due to a side effect of estrogen metabolites.
Keyword Estrogen
Vascular smooth muscle cells
Stress induced premature senescence
Ras
Cellular senescence
Injured arteries
DNA-damage
Atherosclerosis
Inflammation
Protection
Rats
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Australian Institute for Bioengineering and Nanotechnology Publications
 
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Created: Fri, 23 Sep 2011, 15:44:21 EST by Professor Julie Campbell on behalf of Aust Institute for Bioengineering & Nanotechnology