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Dihydrotestosterone Decreases Tumor Necrosis Factor- and Lipopolysaccharide-Induced Inflammatory Response in Human Endothelial Cells

Department of Pharmacological Sciences (G.D.N., G.T., P.M.S., A.L.C.) and Institute of Endocrinology (A.P.), Centre of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy; and Center for the Prevention and Therapy of Global Cardiovascular Risk (G.D.N., A.L.C.), Italian Society for the Study of Atherosclerosis, Bassini Hospital, 20092 Cinisello Balsamo, Italy

Address all correspondence and requests for reprints to: Giuseppe Danilo Norata, Ph.D., Department of Pharmacological Sciences, University of Milan, Italy, Via Balzaretti 9, 20133, Milan, Italy. 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 proinflammatory response observed in human endothelial cells.

Design: Human endothelial cells isolated from umbilical cords were incubated with lipopolysaccharide or TNF in the presence or absence of dihydrotestosterone (DHT). mRNA and cellular proteins were processed for gene expression studies, and 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, Milan, Italy.

Results: Lipopolysaccharide and TNF induced VCAM-1 and ICAM-1 mRNA and protein expression, as detected by real-time quantitative PCR, fluorescence-activated cell sorting, and confocal microscopy, but this effect was inhibited 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 such as GRO, granulocyte-macrophage colony-stimulating factor, and TNF. The DHT effect was counteracted by bicalutamide, an antagonist of the androgen receptor. Furthermore, when cells were cotransfected with a Cox-2 promoter or a 3X-NF-B luciferase reporter vector and a plasmid expressing the human androgen receptor, DHT treatment inhibited the increase of the luciferase activity observed with TNF.

Conclusion: DHT could positively regulate endothelial function through the control of the inflammatory response mediated by nuclear factor-B in endothelial cells.

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