Steroid receptor coactivator-3 is required for inhibition of neointima formation by estrogen.

Abstract

BACKGROUND:

The vasoprotective effects of estrogen are mediated by estrogen receptors (ERs). ERs are transcription factors that require coactivators to exert transcriptional activity. The steroid receptor coactivator-3 (SRC-3, also known as pCIP, AIB1, ACTR, and TRAM-1) interacts with estrogen-bound ERs and strongly coactivates the transcription of target genes in cultured cells. This study has characterized the expression of SRC-3 in cardiovascular tissue and the role of SRC-3 in estrogen-dependent vasoprotection from vascular injury.

METHODS AND RESULTS:

Phenotypically normal SRC-3(+/-) mice with a knock-in LacZ reporter were used to characterize SRC-3 expression by X-gal staining within the cardiovascular system. Staining signals were specifically detected in vascular smooth muscle cells and endothelial cells but not in myocardial cells. The role of SRC-3 during vascular remodeling was analyzed using a unilateral carotid ligation model. The extent of neointima formation in SRC-3(-/-) mice was significantly higher than in wild-type mice, and this difference was diminished after depletion of estrogen by ovariectomy. After ovariectomy, neointimal growth in wild-type mice was almost completely inhibited by estrogen treatment but only partially inhibited in SRC-3(-/-) mice. Furthermore, estrogen treatment resulted in reduced inhibition of intimal cell proliferation in SRC-3(-/-) mice.

CONCLUSIONS:

SRC-3 is highly expressed in vascular smooth muscle cells and endothelial cells. The loss of SRC-3 function causes a decrease in sensitivity of estrogen-mediated inhibition of neointimal growth, which may be attributable to an insufficient suppression of vascular cell proliferation. These results indicate that SRC-3 largely facilitates ER-dependent vasoprotective effects under conditions of vascular trauma.

• Authors: Yuhui Yuan, Lan Liao, David A Tulis, Jianming Xu
• Journal: Circulation (Circulation) Vol. 105 Issue 22 Pg. 2653-9 (Jun 04 2002) ISSN: 1524-4539 [Electronic] United States
• PMID: 12045172 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Estrogens
• Trans-Activators
• Estradiol
• Histone Acetyltransferases
• Ncoa3 protein, mouse
• Nuclear Receptor Coactivator 3

Topics

• Animals
• Apoptosis (drug effects)
• Carotid Artery Injuries (drug therapy, metabolism, pathology)
• Cell Count
• Cell Division (drug effects)
• Disease Models, Animal
• Disease Progression
• Endothelium, Vascular (drug effects, metabolism, pathology)
• Estradiol (pharmacology)
• Estrogens (pharmacology)
• Female
• Gene Expression
• Gene Targeting
• Histone Acetyltransferases
• Immunohistochemistry
• Ligation
• Mice
• Mice, Inbred Strains
• Mice, Knockout
• Mice, Mutant Strains
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Nuclear Receptor Coactivator 3
• Ovariectomy
• Trans-Activators (deficiency, genetics, metabolism)
• Tunica Intima (drug effects, injuries, metabolism, pathology)