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Estradiol decreases IGF-1 and IGF-1 receptor expression in rat aortic smooth muscle cells. Mechanisms for its atheroprotective effects

Scheidegger, K J.
Cenni, Bruno
Delafontaine, P.
Published in The Journal of biological chemistry. 2000, vol. 275, no. 49, p. 38921-8
Abstract 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 E(2) 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 ERalpha or ERbeta and treated with 100 nm 17beta-estradiol (E(2)) for 24 h. E(2) treatment decreased basal luciferase activity by 51%, and this effect was dependent on co-expression of ERalpha, whereas no repression was observed with ERbeta. A mutation within the DNA binding domain of the ERalpha abolished the repressor function of the ER receptor. Similarly, E(2) decreased IGF-1R transcription by 21% in rat aortic smooth muscle cells (RASMC), which express endogenous ER. This effect was specific for E(2), because it was inhibited by an antiestrogen and because progesterone did not have any effect on IGF-1R expression in HeLa or RASMC transfected with progesterone receptor. Accordingly, E(2) decreased IGF-1R and IGF-1 mRNA in RASMC by 47% and 33%. Western blot analysis and radioligand binding studies showed that E(2) also dose-dependently decreased IGF-1R protein expression in RASMC by 40% and 30%, respectively, and that IGF-1 protein was reduced by 43%. Repression of IGF-1R promoter activity by a combination of ERalpha and E(2) 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, E(2) down-regulates 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.
Keywords AnimalsAortaCells, CulturedEstradiol/analogs & derivatives/pharmacologyEstrogen Antagonists/pharmacologyEstrogen Receptor alphaEstrogen Receptor betaGene Expression Regulation/drug effects/physiologyHela CellsHumansMuscle, Smooth, Vascular/metabolismPolyunsaturated AlkamidesPromoter Regions, Genetic/drug effectsRatsReceptor, IGF Type 1/geneticsReceptor, IGF Type 2/geneticsReceptors, Estrogen/genetics/physiologyRecombinant Proteins/metabolismTamoxifen/analogs & derivatives/pharmacologyTransfection
PMID: 10982795
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SCHEIDEGGER, K J. et al. Estradiol decreases IGF-1 and IGF-1 receptor expression in rat aortic smooth muscle cells. Mechanisms for its atheroprotective effects. In: The Journal of biological chemistry, 2000, vol. 275, n° 49, p. 38921-8. doi: 10.1074/jbc.M004691200 https://archive-ouverte.unige.ch/unige:4473

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Deposited on : 2009-12-01

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