Estradiol 17-beta represses insulin-like growth factor I receptor expression in smooth muscle cells from rabbit cardiac recipients.
BACKGROUND
A crucial step in cell cycle progression is the activation of the insulin-like growth factor I (IGF-I) receptor (IGF-IR) by its ligand. Earlier, we found estradiol 17-beta treatment of cardiac allograft recipients attenuates transplant arteriosclerosis; this was associated with inhibition of vascular cell proliferation induced by IGF-I. The current study demonstrates regulation of IGF-IR by estradiol 17-beta in vivo and in vitro in recipient native and allograft aorta and in aorta smooth muscle cells (SMCs).


METHODS
Twenty cardiac transplant recipient rabbits were treated with estradiol 17-beta (100 microg/kg/day) or placebo for 6 weeks. IGF-IR expression in the coronary arteries of rabbits was demonstrated by immunohistochemistry. Reverse transcription-polymerase chain reaction and RNase protection assay were used to detect IGF-IR mRNA in rabbit aortas and cultured aortic SMCs in the presence or absence of estradiol 17-beta in vitro. IGF-I-induced cell proliferation was performed with the aorta explants and aorta SMCs from estradiol- or placebo-treated rabbits.


RESULTS
Estradiol 17-beta treatment of rabbits significantly inhibited IGF-IR expression in the allograft coronary arteries and abrogated cell proliferation induced by IGF-I in the allograft aorta compared with placebo-treated recipients (65.4+/-5% vs. 500+/-139%, P<0.002). Expression of IGF-IR mRNA in the allograft aorta of placebo-treated recipients was significant higher than that of the native aorta (286+/-56%, P<0.02). Estradiol treatment significantly inhibited IGF-IR mRNA expression in the aorta versus that of the placebo-treated recipients (65+/-8.5% vs. 140+/-23%, P<0.02). Repression of IGF-IR mRNA expression in aortic SMCs by estradiol in vitro was in a concentration-dependent manner (P<0.02).


CONCLUSIONS
Repression of IGF-IR protein and mRNA by estradiol 17-beta in vivo and in vitro suggest that one of the mechanisms of estradiol inhibition of SMC proliferation and transplant arteriosclerosis is down-regulation of IGF-IR.
Lou
H
H
Department of Surgery, Georgetown University Medical Center, Washington, District of Columbia 20007, USA.
Ramwell
P W
PW
Foegh
M L
ML
D000818:Animals; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism; D004958:Estradiol / Q000502:physiology*; D016027:Heart Transplantation / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis; D011817:Rabbits; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
D004958:Estradiol; D012313:RNA; D017526:Receptor, IGF Type 1