Dehydroepiandrosterone (DHEA) Inhibition of Monocyte Binding by Vascular Endothelium Is Associated With Sialylation of Neural Cell Adhesion Molecule

Abstract

Rationale: Adhesion of monocytes to vascular endothelium is necessary for atheroma formation. This adhesion requires binding of endothelial neural cell adhesion molecule (NCAM) to monocyte NCAM. NCAM:NCAM binding is blocked by sialylation of NCAM (polysialylated NCAM; PSA-NCAM). Since estradiol (E2) and dihydrotestosterone (DHT) induced PSA-NCAM and decreased monocyte adhesion, in consideration of possible clinical applications we tested whether their prohormone dehydroepiandrosterone (DHEA) has similar effects. Experimental: (1) DHEA was administered to cultured human coronary artery endothelial cells (HCAECs) from men and women. Monocyte binding was assessed using fluorescence-labeled monocytes. (2) HCEACs were incubated with E2, DHT, DHEA alone, or with trilostane, fulvestrant or flutamide. Expression of PSA-NCAM was assessed by immunohistochemistry and Western blotting. Results: Dehydroepiandrosterone inhibited monocyte adhesion to HCAECs by !50% (P < .01). Fulvestrant or flutamide blockade of DHEA's inhibition of monocyte binding appeared to be gender dependent. The DHEA-induced expression of PSA-NCAM was completely blocked by trilostane. Conclusions: In these preliminary in vitro studies, DHEA increased PSA-NCAM expression and inhibited monocyte binding in an estrogen-and androgen receptor-dependent manner. Dehydroepiandrosteroneappears to act via its end metabolites, E2 and DHT. Dehydroepiandrosterone could furnish clinical prevention against atherogenesis and arteriosclerosis.

Dehydroepiandrosterone Protects Endothelial Cells against Inflammatory Events Induced by Urban Particulate Matter and Titanium Dioxide Nanoparticles

“…Similar results have been found by Curatola and collaborators [10]. They observed that DHEA inhibited the adhesion of monocytes to cultured human coronary artery endothelial cells (HCAEC), in an estrogen- and androgen-receptor-dependent manner.…”

Sex Steroids Block the Initiation of Atherosclerosis

“…While more study is required, it appears that these effects of sex steroids may break the very nexus of atherogenesis, as portrayed in Figure 7, thereby acting as a cardioprotective agent before the development of atherosclerotic disease. 38 showing the result of incubating monocytes on a lawn of (female) human arterial endothelial cells (HAECs) and washing away the nonadherent cells after 90 minutes. The antiestrogen SERM fulvestrant blocked the E 2 effect but not the testosterone effect.…”

“…38 Selected results are shown in Figures 5 and 6. In all cases, the induction of PSA-nCAM was documented by histochemistry.…”

“…In all cases, the induction of PSA-nCAM was documented by histochemistry. 38 Further studies testing monocyte pretreatment and shearing assays are continuing.…”

Oxidative and electrophilic structural modification and catalytic regulation of human hydroxysteroid sulfotransferase 2a1 (hsult2a1)

“…A membrane bound receptor was identified in endothelial cells, heart, liver and kidney which reacts with DHEA specifically with high affinity and can lead to stimulation of endothelial nitric synthase (eNOS) expression as well as activity (Liu and Dillon, 2002). This can further lead to downstream effects including stimulating endothelial proliferation, increasing flow-mediated dilation (Williams et al, 2004), reducing adhesion of monocytes to endothelial cells, amelioration inflammatory responses, and the production of ROS (Kasperska-Zajac et al, 2009;Curatola et al, 2012). Clinical studies have revealed a protective effect of DHEA against cardiovascular diseases including ischemic heart disease and congestive heart failure (Beer et al, 1996;Feldman et al, 2001;Shufelt et al, 2010).…”