Monocyte CD40 expression in young healthy female smokers and/or oral contraceptives users without additional risk factors for atherosclerosis.

OBJECTIVE: Atherosclerosis, as an inflammatory disease, is characterized by pathologically altered levels of cytokines. We investigated whether smoking and/or oral contraceptives (OCs) affect the CD40/CD40L plasma levels and expression in young females without other risk factors for atherosclerosis. PATIENTS AND METHODS: A case-control single-center design was used. Expression levels of CD40/CD40L were analyzed in healthy non-pregnant, pre-menopausal, non-smoking women who did not take OCs (n=49), women who currently smoke and take OCs (n=40), and women who are only smokers (n=40) or currently take OCs (n=42). RESULTS: In OC users, there was a significant increase in CD40 mRNA expression in circulating monocytes as compared with smokers and control group. However, there were no significant differences in CD40 mRNA expression in monocytes between smokers and non-smokers. Interestingly, CD40 mRNA expression in women taking OCs and currently smoking was significantly decreased compared to only OC users (p<0.001). With regard to plasma CD40 levels there were significant differences between OC-users and control group. However, contrary to our expectations, there were no significant differences in expression levels of CD40L between four groups. In vitro experiments demonstrated enhanced CD40 mRNA and surface expression in human monocyte-derived macrophages stimulated with estrogens. Furthermore, nicotine pretreatment led to a suppression of estrogens stimulated CD40 induction. CONCLUSIONS: In young healthy females without additional risk factors for atherosclerosis, OCs, but not smoking, are associated with dramatic changes in CD40 gene and plasma levels. These findings may be providing an important link between OCs and enhancement of pro-inflammatory and atherothrombotic conditions in healthy women.

Nicotine modulation of factor VII activating protease (FSAP) expression in human monocytes.

AIM: Factor VII activating protease (FSAP) is a plasma serine protease involved in hemostasis and remodeling processes. Increased levels of circulating FSAP during pregnancy and in women using oral contraceptives (OCs) indicate that the hormonal status critically influences FSAP expression. In this respect, the aim of this study was to quantify nicotine modulation of FSAP expression in human monocytes/macrophages isolated from healthy female smokers and non-smokers, and from women who use OCs and smoke. METHODS: FSAP concentration and activity were measured in plasma samples obtained from healthy non-pregnant, pre-menopausal, non-smoking women who did not use OCs (n=69), non-pregnant, pre-menopausal women who currently smoke and use OCs (n=43), and women who are only smokers (n=40) or currently use OCs (n=48). Expressions of FSAP mRNA and protein in monocytes isolated from healthy non-pregnant female or healthy male donors were analyzed. RESULTS: Strongest circulating FSAP concentration and activity occurred in women with combined smoking and use of OCs compared to the control group. Enhanced FSAP levels were also observed in smoking women when compared to non-smokers. Ex vivo experiments demonstrated enhanced FSAP expression in monocytes isolated from women using OCs and currently smoking. Nicotine enhanced FSAP mRNA and protein levels in monocytes. CONCLUSIONS: Monocytes from healthy female smokers show a constitutively enhanced FSAP expression and this effect could be replicated in vitro by stimulating monocytes with nicotine. The upregulation of FSAP due to nicotine and OC usage may be linked to a higher incidence of arteriothromboembolic diseases related to their usage.

Factor seven ativating potease (FSAP) levels during normal pregnancy and in women using oral contraceptives.

INTRODUCTION: Factor seven activating protease (FSAP) is a plasma serine protease involved in haemostasis and remodeling processes. We have investigated whether pregnancy or the use of oral contraceptives (OCs) influences circulating FSAP levels. The effect of female sex hormones on FSAP expression in cultured cells was also determined. MATERIALS AND METHODS: FSAP levels and activity was measured in plasma samples obtained at different gestation stages from healthy pregnant women (n=101), from non-pregnant women, pre-menopausal women who currently use OCs (n=48), and non-pregnant women who did not use OCs (n=69). RESULTS: In late pregnancy the plasma FSAP antigen (median 2.28 PEU/ml [range 1.11 to 2.62 PEU/ml]; p<0.001 vs control group) and activity (median 2.98 PEU/ml [range 1.05 to 4.24 PEU/ml]; p<0.001 vs control group) was significantly higher compared with levels in non-pregnant women and remained elevated after delivery. Plasma FSAP levels in women using OCs was also significantly elevated compared to the control group. Ex vivo experiments demonstrated enhanced FSAP expression in monocytes isolated from women using OCs. In vitro experiments showed that FSAP mRNA levels were strongly induced by estradiol in monocytes but not in hepatocytes. CONCLUSIONS: Increased levels of circulating FSAP in pregnancy and in women using OCs indicate that hormonal status critically influences FSAP expression. Hormonal influences could be observed in monocytes in vivo and ex-vivo but not in hepatocytes indicating cell-specific regulation. Future studies designed to investigate the role of FSAP in haemostasis and remodeling processes should consider the role of female sex hormones on FSAP expression.