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Submitted on July 25, 2005
Accepted on November 21, 2005
and lipopolysaccharide induced inflammatory response in human endothelial cells
Department of Pharmacological Sciences, University of Milan, Italy; Institute of Endocrinology, Centre of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy; Center for the Prevention and therapy of Global cardiovascular risk, Italian Society for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy
* To whom correspondence should be addressed. E-mail: Danilo.Norata{at}unimi.it.
Context. An increasing body of evidence suggests that testosterone may exert beneficial effects on the development of atherosclerosis. It was suggested that testosterone may act after conversion into estradiol and activation of the estrogen receptors, however a direct role of androgens on the vascular wall has been proposed.
Objective. We investigated the effects of dihydrotestosterone on the pro-inflammatory response observed in human endothelial cells.
Design. Human endothelial cells isolated from umbilical cords were incubated with LPS or TNF
in the presence or absence of DHT. mRNA and cellular proteins were processed for gene expression studies, transient transfection experiments were performed to investigate molecular mechanisms involved in the effects observed.
Setting. These studies took place at the Department of Pharmacological Sciences, University of Milan, Italy.
Results. LPS and TNF induced VCAM-1, and ICAM-1 mRNA and protein expression, as detected by Q-real time PCR, FACS and confocal microscopy, but this effect was reverted when cells were incubated with DHT. In addition DHT inhibited mRNA expression of IL-6, MCP-1, CD40, TLR4, PAI-1 and Cox-2 and the release of cytokines and chemokines as GRO, GM-CSF and TNF. The DHT effect was counteracted by bicalutamide, an antagonist of the androgen receptor. Furthermore when cells were co-transfected with a Cox-2 promoter or a 3xNF-kB luciferase reporter vector and a plasmid expressing the human androgen receptor, DHT treatment inhibited the increase of the luciferase activity observed with TNF.
Conclusion. Dihydrotestosterone could positively regulate endothelial function through the control of the inflammatory response mediated by NF-kB in endothelial cells.
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