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Papers In Press, published online ahead of print September 11, 2000
Division of Cardiology, University Hospital of Geneva, 1211, Geneva 14
Corresponding Author: patrice.delafontaine{at}hcuge.ch
Insulin-like growth factor (IGF-1) is a potent mitogen for vascular smooth muscle cells. Both IGF-1 and its receptor have been shown to be highly expressed in atherosclerotic lesions. Here we investigated whether part of the vasculoprotective properties of E2 may be mediated by its negative regulation of the IGF-1 system. HeLa cells which do not contain endogenous estrogen receptors (ER) were transiently transfected with IGF-1R promoter constructs with or without a plasmid encoding human ER or ER and treated with 100 nM 17-estradiol (E2) for 24 h. E2 treatment decreased basal luciferase activity by 51% and this effect was dependent on co-expression of ER, whereas no repression was observed with ER. A mutation within the DNA binding domain of the ER abolished the repressor function of the ER receptor. Similarly, E2 decreased IGF-1R transcription by 21% in rat aortic smooth muscle cells (RASMC) which express endogenous ER. This effect was specific for E2, since it was inhibited by an antiestrogen and since progesterone did not have any effect on IGF-1R expression in HeLa or RASMC transfected with progesterone receptor. Accordingly, E2 decreased IGF-1R and IGF-1 mRNA in RASMC by 47% and 33%. Western blot analysis and radioligand binding studies showed that E2 also dose-dependently decreased IGF-1R protein expression in RASMC by 70% and 30%, respectively, and that IGF-1 protein was reduced by 43%. Repression of IGF-1R promoter activity by a combination of ER and E2 did not appear to be mediated via direct binding of ER to the IGF-1R promoter but rather by inhibition of SP1 binding to the IGF-1R promoter. Thus, E2 downregulates IGF-1R and IGF-1 expression in vascular smooth muscle cells. This may have important implications for the understanding of the beneficial effects of estrogen in the cardiovascular system.
J. Biol. Chem, 10.1074/jbc.M004691200
Submitted on May 31, 2000
Revised on August 22, 2000
Accepted on September 11, 2000
Estradiol decreases IGF-1 and IGF-1 receptor expression in rat aortic smooth muscle cells: Mechanisms for its atheroprotective effects
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