Background: An increasing body of evidence suggests that testosterone may exert beneficial effects against the development of atherosclerosis. These effects are thought to be the consequence of its conversion into estradiol and the activation of the estrogen receptors; however a direct role of androgens, such as dihydrotestosterone, has also been proposed. More recently, it has been shown that the transformation of the dihydrotestosterone to 5?-androstane-3?,17?-diol (3?-diol) and 5?-androstane-3?,17?-diol (3?-Adiol), generates two molecules unable to bind the androgen receptor, but with a high affinity for the estrogen receptors (ERs) in particular the ? isoform. As the actions of testosterone may result from the balance between androgenic and estrogenic molecules originating from its catabolism, we investigated the effects of the 3?-Adiol on inflammatory responses in vitro in human endothelial cells and ex vivo in mice aortas. Methods and results: 3?-Adiol reverts the pro-inflammatory gene expression pattern induced by TNF-? in HUVECs as determined by a cDNA microrray approach. Q-real-time PCR and protein array approaches confirmed that TNF-?-induced ICAM-1, VCAM-1 and ELAM-1 as well as MCP-1 and IL-6 induction was affected upon 3?-Adiol pre-incubation. ICI 182780, an estrogen receptor antagonist and R,R-THC, an estrogen receptor ? antagonist, counteracted the effect of 3?-Adiol while bicalutamide, an androgen receptor antagonist, had minor effects. 3?-Adiol exerted a similar action on macrophages. Finally in castrated male mice, 3?-Adiol significantly counteracted the LPS mediated mRNA induction of IL-6, ELAM-1and PECAM-1 in the aortas. Conclusion: 3?-Adiol reverts in vitro the TNF-? and LPS induced pro-inflammatory activation of endothelial cells and macrophages. 3?-Adiol in vivo modulates the inflammatory response induced by LPS in the arterial vascular wall. © 2010 Elsevier Ireland Ltd.
The androgen derivative 5?-androstane-3?,17?-diol inhibits tumor necrosis factor ? and lipopolysaccharide induced inflammatory response in human endothelial cells and in mice aorta
Cattaneo Paola;
2010
Abstract
Background: An increasing body of evidence suggests that testosterone may exert beneficial effects against the development of atherosclerosis. These effects are thought to be the consequence of its conversion into estradiol and the activation of the estrogen receptors; however a direct role of androgens, such as dihydrotestosterone, has also been proposed. More recently, it has been shown that the transformation of the dihydrotestosterone to 5?-androstane-3?,17?-diol (3?-diol) and 5?-androstane-3?,17?-diol (3?-Adiol), generates two molecules unable to bind the androgen receptor, but with a high affinity for the estrogen receptors (ERs) in particular the ? isoform. As the actions of testosterone may result from the balance between androgenic and estrogenic molecules originating from its catabolism, we investigated the effects of the 3?-Adiol on inflammatory responses in vitro in human endothelial cells and ex vivo in mice aortas. Methods and results: 3?-Adiol reverts the pro-inflammatory gene expression pattern induced by TNF-? in HUVECs as determined by a cDNA microrray approach. Q-real-time PCR and protein array approaches confirmed that TNF-?-induced ICAM-1, VCAM-1 and ELAM-1 as well as MCP-1 and IL-6 induction was affected upon 3?-Adiol pre-incubation. ICI 182780, an estrogen receptor antagonist and R,R-THC, an estrogen receptor ? antagonist, counteracted the effect of 3?-Adiol while bicalutamide, an androgen receptor antagonist, had minor effects. 3?-Adiol exerted a similar action on macrophages. Finally in castrated male mice, 3?-Adiol significantly counteracted the LPS mediated mRNA induction of IL-6, ELAM-1and PECAM-1 in the aortas. Conclusion: 3?-Adiol reverts in vitro the TNF-? and LPS induced pro-inflammatory activation of endothelial cells and macrophages. 3?-Adiol in vivo modulates the inflammatory response induced by LPS in the arterial vascular wall. © 2010 Elsevier Ireland Ltd.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
