Effects of estradiol on transcriptional profiles in atherosclerotic iliac arteries in ovariectomized cynomolgus macaques.
ABSTRACT OBJECTIVE: This study aimed to assess the in vivo effects of estradiol treatment on arterial gene expression in atherosclerotic postmenopausal female monkeys. METHODS: Eight ovariectomized cynomolgus monkeys were fed atherogenic diets for 6.5 years. The left iliac artery was biopsied before randomization to the estradiol group (human equivalent dose of 1 mg/d, n = 4) or the vehicle group (n = 4) for 8 months. The right iliac artery was obtained at necropsy. Transcriptional profiles in pretreatment versus posttreatment iliac arteries were compared to assess the responses of atherosclerotic arteries to estradiol. RESULTS: Iliac artery plaque size did not differ between the estradiol group and the placebo group at baseline or during the treatment period. Nevertheless, estradiol treatment was associated with increased expression of 106 genes and decreased expression of 26 genes in the iliac arteries. Estradiol treatment increased the expression of extracellular matrix genes, including the α1 chain of type I collagen, the α2 chain of type VI collagen, and fibulin 2, suggestive of an increase in the proportion or phenotype of smooth muscles or fibroblasts in lesions. Also increased were components of the insulin-like growth factor pathway (insulin-like growth factor 1, insulin-like growth factor binding protein 4, and insulin-like growth factor binding protein 5) and the Wnt signaling pathway (secreted frizzled-related protein 2, secreted frizzled-related protein 4, low-density lipoprotein receptor-related protein 6, and Wnt1-inducible signaling pathway protein 2). CONCLUSIONS: Estradiol treatment of monkeys with established atherosclerosis affected iliac artery gene expression, suggesting changes in the cellular composition of lesions. Moreover, it is probable that the presence of atherosclerotic plaque affected the gene expression responses of arteries to estrogen.
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ABSTRACT: Background and Aims To examine effects of equol, the soy phytoestrogen metabolite, on gene expression in the monkey iliac artery. Methods and Results A high fat/high cholesterol diet was fed to eight ovariectomized cynomolgus monkeys for 6.5 years. After biopsy of the left iliac artery, the animals were randomized to two treatment groups for 8 months; the treatment groups were equol (23.7 mg/100 g diet, n=4) and vehicle (n=4). The right iliac artery was removed at necropsy. Gene expression in the iliac arteries in response to equol was determined by DNA microarray. Comparison of atherosclerotic lesions and plasma lipids at pre- versus post-equol treatment time points and in vehicle versus equol treatment groups did not identify any significant differences. Despite the lack of effect of equol on these parameters, 59 genes were down-regulated and 279 were up-regulated in response to equol. Comparison of these data to previous work identified 10 genes regulated in opposite directions by equol compared to presence of atherosclerosis plaque (Menopause 2011;18:1087-1095) and 55 genes differentially expressed in the same direction in response to both equol and estradiol (Eyster et al., Menopause 2013; in press). Conclusions Similar responses of genes to both equol and estradiol may reflect the extent to which equol serves as a natural selective estrogen receptor modulator in the arteries. Opposite responses of 10 genes to equol versus the presence of atherosclerosis implicates those genes in the potential protective effects of equol in arteries.Nutrition, metabolism, and cardiovascular diseases: NMCD 01/2013; DOI:10.1016/j.numecd.2013.09.014 · 3.88 Impact Factor
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ABSTRACT: Fibulins are a group of extracellular matrix proteins of which many are present in high amounts in the cardiovascular system. They share common biochemical properties and are often found in relation to basement membranes or elastic fibers. Observations in humans with specific mutations in fibulin genes, together with results from genetically engineered mice and data from human cardiovascular tissue suggest that the fibulin family of proteins play important functional roles in the cardiovascular system. Moreover, fibulin-1 circulates in high concentrations in plasma and may function as a cardiovascular disease marker. © 2014 Elsevier Inc. All rights reserved.01/2014: pages 245-265; Elsevier.