| B a ckg ro u n dEstrogen replacement therapy is attracting wide interest, both interms of its benefits and risks. Estrogens relieve menopausalsymptoms and play a major role in preventing the most importanthealth concerns of postmenopausal women, i.e., coronary arterydisease.Relative to men, women are protected against atherosclerosisand its clinical complications until after they reach menopause, whencessation of ovarian cyclicity results in reduced circulating estrogenlevels. Estrogen replacement therapy reduces the incidence ofcoronary heart disease in post-menopausal women, and inhibits theprogression of diet-induced coronary artery atherosc lerosis inovariectomized cynomolgus mon-keys(Macaca fascicul ari s)and otheranimal models by 50% or more.In both cases, only a smaIl portion ofthe beneficial effect of estrogen can be explained by effects onlipoproteins and other traditional risk factors .These findings andothers suggest that estrogen may have direct, and perhapsreceptor-dependent,effects on arterial metaboIism which areimportant in this atheroprotection. However. the mechanism by whichestrogen acts on the vascular wall to inhibit atherogenesis is notkno wn.The existence of estrogen receptors (ER)in vascular tissues hasbeen investigated for many years, although their role in vascularmetabolism is stiIl poorly understood. Early methods usedradio-labeled estrogen to demonstrate hormone binding in arterialtissues. In cultured aortic endothelial cells and in SMCs .ER mRNAand protein has been detected in cultured rat aortic SMCs, inculturecd human mammary artery and saphenous vein SMCs, and ERmRNA has been found in nonhuman primate aorta. In addition, recentstudies have demonstrated that ER protein and mRNA are present inhuman and nonhuman primate coronary arteries, respectively.Theability of native ER to regu1ate transcription in arterial SMCs hasbeen demonstrated through transient transfection assays withestrogen responsive reportr constructs.Recently,a novel estrogen receptor (ER-0) has been discovered.This new receptor is the product of a distinct gene and is not a splicevariant of the traditional ER,which is now being referred to as ERQ .The sequences of the transcripts for ER-0 have been reported forboth rat and human. ER-0 is similar to traditional ER Q, showing~95% homology in the DNA binding domain and ~55% homology inthe ligand binding domain (within each species).In the rat, in situhybridization studies demonstrated that rat ER-6 was expressed inreproductive tissues of both males and females, with highestexpression in the prostate epithelial ceIls and ovarian granulosa ce1ls.The receptor was transcriptionalIy activated by estradiol, andcompetition curves demonstrate that the receptor has similar ligandbinding characteristics for estradiol as ER Q. Studies with the humanER-D also demonstrated that the transcriptional activity could beinhibited with the ER Q antagonist ICI l64,384.Northern blotanalyses showed highest levels of ER-0 in the testis, ovary, andthymus,although expression was also observed in spleen, prostate,intestine, and peripheral blood monocytes. More recent studies havedemonstrated that ER-P is expressed in a variety of animal tissues.that the relative expression of ER-0mRNA varies greatly betweendifferent tissues.Coronary artery were not examined in thesestudies.No information about the distribution of ER-6mRNA inc ard iovasc ul ar tis sue s.The purpose of the present study was to determine if ER-DmRNA is expressed in the coronary arteries and other cardiovasculartissues of human fetal, and to test the relative expression of ER-9mRNA to elucidate whether differences exist in cardiovascuIarti s s ues.METH ODSTissue collection fOr RNA isolationCardiovascular tissues were derived from the human fetal atnecropsy. Ovary was coIIected at the time of ovariectomy. From eachtissue, 0.5 g samples were... |
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