Steroid Sulfatase and Estrogen Sulfotransferase in the Atherosclerotic Human Aorta

Abstract

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 ...

3β-Hydroxysteroid Dehydrogenase in Human Aorta

“…It has been reported that the amounts of steroidogenic enzymes related to in situ estrogen production were significantly higher in female aorta than that in male aorta [10,14]. Results of our present study also indicated that this intracrine mechanism enhances or facilitates steroid hormone effects in human aorta especially in female.…”

“…Both steroidogenic endocrine glands and local synthesis are currently considered to contribute to the pool of progesterone present in brain and peripheral nerves. We previously demonstrated in situ estrogen synthesis in human aorta, especially in female aorta [10]. It has also been reported that progesterone plays an important role in athero-protection in human VSMCs via progesterone receptors (PRs) [16], in the same fashion as estrogen via estrogen receptors (ERs).…”

“…Results of our present study also suggest the importance of local synthesis of progesterone in the human aorta, especially in female aorta for athero-protection, as in human nervous system. In addition, we previously reported that expression levels of in situ estrogen synthesizing and/or metabolizing enzymes may be significantly associated with the degree of atherosclerotic changes in female aorta, which may be related to cytokines produced in situ in human atherosclerotic lesions [10]. Previous reports also documented that some cytokines and hormones were involved in regulation of 3b-HSD expression in breast cancer and/or testis [17,18].…”

“…In addition, the samples were categorized into two groups based on the degree of atherosclerosis. The classification of atherosclerosis defined by the American Heart Association (AHA) in 1995 was employed in this study in order to semi-quantify the degree of atherosclerotic changes in each specimen, utilizing macroscopic findings at the time of autopsy and subsequent microscopic findings [9,10]. This classification was based on the fact that in the groups with advanced atherosclerotic changes, clinical complications may develop suddenly compared to those with early atherosclerotic changes [9,10].…”

“…The classification of atherosclerosis defined by the American Heart Association (AHA) in 1995 was employed in this study in order to semi-quantify the degree of atherosclerotic changes in each specimen, utilizing macroscopic findings at the time of autopsy and subsequent microscopic findings [9,10]. This classification was based on the fact that in the groups with advanced atherosclerotic changes, clinical complications may develop suddenly compared to those with early atherosclerotic changes [9,10]. In this study, with regard to the degree of atherosclerotic changes, aortic specimens were classified into the following two categories of atheroma score: mild atherosclerosis, corresponding to group I to III in the AHA classification; advanced atherosclerosis, corresponding to group IV to VI in the AHA classification (18 mild atherosclerosis, 10 severe atherosclerosis).…”