Androgen Receptor Expression Is Greater in Macrophages From Male Than From Female Donors

Abstract

Background-Male sex is an independent risk factor for the extent and severity of atherosclerosis. The influence of androgens on foam cell formation, a key event in atherogenesis, has not yet been investigated. Methods and Results-Primary human monocytes were allowed to differentiate into macrophages. RNA was then extracted from healthy male-donor (nϭ8) and premenopausal female-donor (nϭ8) macrophages, and message for the androgen receptor (AR) was examined by RT-PCR. There was a significantly higher level of AR mRNA in macrophages isolated from men than in those from women (0.64Ϯ0.06 versus 0.15Ϯ0.02 amol/g total RNA; PϽ0.001). AR mRNA levels were similar in macrophages from postmenopausal and premenopausal women (Pϭ0.16). The functional consequence of this sex difference was then explored. Lipid-loading studies were performed on male (nϭ9) macrophages treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor-mediated increase in macrophage cholesteryl ester content (109Ϯ10%, 117Ϯ3%, and 120Ϯ4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of control, Pϭ0.002; 95Ϯ8% for DHT with hydroxyflutamide, Pϭ0.58 versus controls). By contrast, there was no significant effect of androgen on lipid loading in female-donor macrophages (PϾ0.2 versus controls). Conclusions-Sex differences in androgen-mediated macrophage lipid loading may contribute to the greater prevalence and severity of atherosclerosis in men. en have an earlier onset and higher incidence of atherosclerosis than women. 1 The potential protective effects of estrogens on vascular structure and function have been studied extensively. Much less work, however, has addressed the possible effects of androgens on atherogenesis. In animal models, androgen treatment may increase plaque formation in the aorta and coronary vessels. 2,3 Furthermore, in humans, we have recently demonstrated that androgens enhance monocyte adhesion to endothelial cells 4 and are associated with impaired vascular reactivity. 5 Foam cell formation is a key early event in atherosclerosis and is largely due to the uptake of modified lipoproteins, principally LDL, by peripheral blood monocyte-derived macrophages (MDMs) in the arterial wall. 6,7 The possibility that androgen receptors (ARs) and androgen-related intracellular pathways may be involved in the process of lipid loading and foam cell formation in atherosclerosis has not been explored previously. We therefore investigated whether the AR is expressed in primary human MDMs and whether there is a sex difference in its expression and have examined the biological effects of androgen stimulation on cholesteryl ester (CE) formation/lipid loading in these cells. Methods Isolation of Human MonocytesWhite cell concentrates (Red Cross Blood Bank) were obtained from the peripheral blood of individual healthy men (20 to 58 years old) and premenopausal (18 to 45 years old) and postmenopausal (45, 55, and 72 years old) women. The postmenopau...

Androgen-replacement therapy depresses the ex vivo production of inflammatory cytokines by circulating antigen-presenting cells in aging type-2 diabetic men with partial androgen deficiency

“…Androgen receptors or their mRNA have been detected in both CD4+ and CD8+ T cells as well as in macrophages (Liva & Voskuhl 2001, Tanriverdi et al 2003 and it has been shown that testosterone may directly induce cytokine gene expression on CD4+ T lymphocytes via androgen receptors (Liva & Voskuhl 2001). Monocyte-derived macrophages also express androgen receptors (McCrohon et al 2000) and these cells may metabolize testosterone to 5 -dihydrotestosterone (Araneo et al 1991). In this regard, treatment of mice with flutamide, an androgen-receptor blocker, restores previously depressed cellular immunity after brain injury (Messingham et al 2001).…”

Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall

“…11 Androgen and estrogen receptors are present in vascular smooth muscle cells, 11,12 human macrophages, human megakaryocytes, and platelets. 13,14 Interestingly, McCrohon et al 15 found sex-specific differences in androgen receptor expression in human macrophages. Furthermore, in human megakaryocytes, the androgen receptor was upregulated by testosterone at a concentration of 10 nmol/L, whereas downregulation occurred at a concentration of 100 nmol/L.…”

Complete Androgen Insensitivity Syndrome

“…Second, some effects of sex steroids (eg, androgens) on the meibomian gland may be sex specific, given that certain actions of these hormones on the accumulation of particular lipid species have been shown to occur only in males or females. 46,47 These sex-associated responses could also lead to differences in ion expression. Third, we 6,48 previously showed that the polar lipid profiles in meibomian gland secretions of women are not uniform and seem to fall into 2 major patterns.…”