Effect of Estrogen and Progesterone on Gene Expression of Growth Regulatory Molecules and Proto-Oncogene in Vascular Smooth Muscle Cells.

Okubo, Tomoharu; Urabe, Mamoru; Iwasa, Kinuko; Yokota, Kazuaki; Kikuchi, Noriko; Yamamoto, T.; Honjo, Hideo

doi:10.1507/endocrj.47.205

Cited by 19 publications

(10 citation statements)

References 38 publications

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“…For example, estradiol decreases collagen deposition, whereas it increases the expression of elastin and fibrillin 1 transcripts (19), in agreement with the regulation of the ECM presented in Table 4. Also in agreement with our results (Table 4), estradiol decreases the growth capacity of VSMC through the regulation of complementary signaling pathways (20).…”

Section: Discussionsupporting

confidence: 93%

Sex-specific regulation of gene expression in the aging monkey aorta

Qiu¹,

Tian

Resuello³

et al. 2007

Physiological Genomics

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Although increased vascular stiffness is more prominent in aging males than females, and males are more prone to vascular disease with aging, no study has investigated the genes potentially responsible for sex differences in vascular aging. We tested the hypothesis that the transcriptional adaptation to aging differs in males and females using a monkey model, which is not only physiologically and phylogenetically closer to humans than the more commonly studied rodent models but also is not afflicted with the most common forms of vascular disease that accompany the aging process in humans, e.g., atherosclerosis, hypertension, and diabetes. The transcriptional profile of the aorta was compared by high-density microarrays between young and old males or females (n = 6/group). About 600 genes were expressed differentially when comparing old versus young animals. Surprisingly, <5% of these genes were shared between males and females. Radical differences between sexes were especially apparent for genes regulating the extracellular matrix, which relates to stiffness. Aging males were also more prone than females to genes switching smooth muscle cells from the "contractile" to "secretory" phenotype. Other sex differences involved genes participating in DNA repair, stress response, and cell signaling. Therefore, major differences of gene regulation exist between males and females in vascular aging, which may underlie the physiological differences characterizing aging arteries in males and females. Furthermore, the analyses in young monkeys demonstrated differences in genes regulating vascular structure, implying that the sex differences in vascular stiffness that develop with aging are programmed at an early age.

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Section: Discussionsupporting

confidence: 93%

Sex-specific regulation of gene expression in the aging monkey aorta

Qiu¹,

Tian

Resuello³

et al. 2007

Physiological Genomics

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“…Results of several recent studies have demonstrated that estrogen inhibits proliferation and migration of these transformed VSMCs in vitro described above. 50,51 These findings as well as the results from the present study seem to suggest that estrogens may play an important role in protecting blood vessels such as the abdominal aorta from developing atherosclerosis by possibly suppressing the activity of transformed VSMCs via the actions of ERs. ER␤ has been reported to be predominantly expressed in VSMCs and is thus likely to be involved in the actions of estrogens in these vascular tissues.…”

Section: Discussionsupporting

confidence: 78%

Steroid Sulfatase and Estrogen Sulfotransferase in the Atherosclerotic Human Aorta

Nakamura

Miki

Suzuki

et al. 2003

The American Journal of Pathology

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Various epidemiological studies have demonstrated a relatively low incidence of cardiovascular events in premenopausal women and its marked increment after menopause. In addition, estrogens have been postulated to exert direct anti-atherogenic effects via binding to estrogen receptors in vascular smooth muscle cells (VSMCs). However, not all postmenopausal women develop atherosclerosis despite decreased levels of serum estrogen. Therefore, we believe it is important to examine the status of estrogen metabolism in situ in the human cardiovascular system. Estrone sulfate (E1S) is a major circulating plasma estrogen that is converted into the biologically active estrogen, estrone (E1) by steroid sulfatase (STS). E1 is also sulfated and reverted into E1S by estrogen sulfotransferase (EST). These two enzymes have recently been shown to play important roles in the in situ estrogen actions of estrogen-dependent human tissues and various sex steroid-dependent tumors. STS and EST, however, have not been studied in detail in the human vascular system associated with atherosclerotic changes. In the present study, we evaluated the relative abundance of STS-and ESTimmunoreactive protein and mRNA expression in human aorta using immunohistochemistry and reverse transcription followed by quantitative polymerase chain reaction in addition to enzyme activity. STS expression levels were found to be significantly higher in the VSMCs obtained from female aortas with mild atherosclerotic changes than in those with severe atherosclerotic changes and in male aortas regardless of atherosclerotic changes. EST expression levels in the VSMCs of these aortas, however, were significantly higher in female aortas with severe atherosclerotic changes and in male aortas than in female aortas with mild atherosclerotic changes. We believe it is important to examine factors regulating the expression and activity of these estrogen-metabolizing enzymes in the human aorta. Various cytokines have been proposed to function as regulators of these enzymes in other tissues. In the present study, we studied the effects of interleukin (IL)-1␤, known to be produced in human atherosclerotic lesions, on the expression of these enzymes using cultured human VSMCs originally obtained from a female patient. IL-1␤ markedly inhibited the expression of STS mRNA and enzyme activity, but stimulated the expression of EST mRNA and enzyme activity. In addition, IL-1␤ also reduced E2 production from E1S and E1 in VSMCs.Results from the present study seem to suggest that the expression levels of both STS and EST mRNA and activity may be significantly associated with the degree of atherosclerotic changes in the female aorta, which may be related to cytokines produced in situ, such as IL-1␤, in human atherosclerotic lesions. Various epidemiological studies have reported a relatively low incidence of cardiovascular events in premenopausal women and its marked increment after menopause.1 Estrogen has, therefore, been proposed as a cardioprotective agent, especially in women.2 In ...

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“…It is well known that estrogen has directly protective effect on the cardiovascular system [17], [34], [35]. Two types of ER (α and β subtypes) have been identified in VSMCs and endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Two types of ER (α and β subtypes) have been identified in VSMCs and endothelial cells. Several studies have shown that estrogen inhibits the proliferation and migration of VSMCs via ERα binding [17], [35], [36]. Furthermore, the anti-atherosclerotic effects of ERα also can be influenced by the methylation status in its promoter region [18], [19].…”

Section: Discussionmentioning

confidence: 99%

microRNA-152 Mediates DNMT1-Regulated DNA Methylation in the Estrogen Receptor α Gene

et al. 2012

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BackgroundEstrogen receptor α (ERα) has been shown to protect against atherosclerosis. Methylation of the ERα gene can reduce ERα expression leading to a higher risk for cardiovascular disease. Recently, microRNAs have been found to regulate DNA methyltransferases (DNMTs) and thus control methylation status in several genes. We first searched for microRNAs involved in DNMT-associated DNA methylation in the ERα gene. We also tested whether statin and a traditional Chinese medicine (San-Huang-Xie-Xin-Tang, SHXXT) could exert a therapeutic effect on microRNA, DNMT and ERα methylation.Methodology/Principal FindingsThe ERα expression was decreased and ERα methylation was increased in LPS-treated human aortic smooth muscle cells (HASMCs) and the aorta from rats under a high-fat diet. microRNA-152 was found to be down regulated in the LPS-treated HASMCs. We validated that microRNA-152 can knock down DNMT1 in HASMCs leading to hypermethylation of the ERα gene. Statin had no effect on microRNA-152, DNMT1 or ERα expression. On the contrary, SHXXT could restore microRNA-152, decrease DNMT1 and increase ERα expression in both cellular and animal studies.Conclusions/SignificanceThe present study showed that microRNA-152 decreases under the pro-atherosclerotic conditions. The reduced microRNA-152 can lose an inhibitory effect on DNA methyltransferase, which leads to hypermethylation of the ERα gene and a decrease of ERα level. Although statin can not reverse these cascade proatherosclerotic changes, the SHXXT shows a promising effect to inhibit this unwanted signaling pathway.

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Effect of Estrogen and Progesterone on Gene Expression of Growth Regulatory Molecules and Proto-Oncogene in Vascular Smooth Muscle Cells.

Cited by 19 publications

References 38 publications

Sex-specific regulation of gene expression in the aging monkey aorta

Sex-specific regulation of gene expression in the aging monkey aorta

Steroid Sulfatase and Estrogen Sulfotransferase in the Atherosclerotic Human Aorta

microRNA-152 Mediates DNMT1-Regulated DNA Methylation in the Estrogen Receptor α Gene

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