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The androgen derivative 5α-androstane-3β,17β-diol inhibits tumor necrosis factor α and lipopolysaccharide induced inflammatory response in human endothelial cells and in mice aorta

  • Author Footnotes
    1 Both authors contributed equally.
    Giuseppe Danilo Norata
    Correspondence
    Corresponding author at: Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Tel.: +39 02 50318293; fax: +39 02 50318386.
    Footnotes
    1 Both authors contributed equally.
    Affiliations
    Department of Pharmacological Sciences, Università degli Studi di Milano, Italy

    Center for the Study of Atherosclerosis, Italian Society for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy
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  • Author Footnotes
    1 Both authors contributed equally.
    Paola Cattaneo
    Footnotes
    1 Both authors contributed equally.
    Affiliations
    Department of Pharmacological Sciences, Università degli Studi di Milano, Italy

    IRCCS Multimedica, Milan, Italy
    Search for articles by this author
  • Angelo Poletti
    Affiliations
    Department of Endocrinology, Pathophysiology and Applied Biology, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy
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  • Alberico Luigi Catapano
    Affiliations
    Department of Pharmacological Sciences, Università degli Studi di Milano, Italy

    Center for the Study of Atherosclerosis, Italian Society for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy

    IRCCS Multimedica, Milan, Italy
    Search for articles by this author
  • Author Footnotes
    1 Both authors contributed equally.

      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 5α-androstane-3α,17β-diol (3α-diol) and 5α-androstane-3β,17β-diol (3β-Adiol), generates two molecules unable to bind the androgen receptor, but with a high affinity for the estrogen receptors (ERs) in particular the β 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 3β-Adiol on inflammatory responses in vitro in human endothelial cells and ex vivo in mice aortas.

      Methods and results

      3β-Adiol reverts the pro-inflammatory gene expression pattern induced by TNF-α in HUVECs as determined by a cDNA microrray approach. Q-real-time PCR and protein array approaches confirmed that TNF-α-induced ICAM-1, VCAM-1 and ELAM-1 as well as MCP-1 and IL-6 induction was affected upon 3β-Adiol pre-incubation. ICI 182780, an estrogen receptor antagonist and R,R-THC, an estrogen receptor β antagonist, counteracted the effect of 3β-Adiol while bicalutamide, an androgen receptor antagonist, had minor effects. 3β-Adiol exerted a similar action on macrophages. Finally in castrated male mice, 3β-Adiol significantly counteracted the LPS mediated mRNA induction of IL-6, ELAM-1and PECAM-1 in the aortas.

      Conclusion

      3β-Adiol reverts in vitro the TNF-α and LPS induced pro-inflammatory activation of endothelial cells and macrophages. 3β-Adiol in vivo modulates the inflammatory response induced by LPS in the arterial vascular wall.

      Keywords

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      References

        • Wu F.C.
        • von Eckardstein A.
        Androgens and coronary artery disease.
        Endocrinol Rev. 2003; 24: 183-217
        • Littleton-Kearney M.
        • Hurn P.D.
        Testosterone as a modulator of vascular behavior.
        Biol Res Nurs. 2004; 5: 276-285
        • Nathan L.
        • Shi W.
        • Dinh H.
        • et al.
        Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase.
        Proc Natl Acad Sci USA. 2001; 98: 3589-3593
        • Malkin C.J.
        • Pugh P.J.
        • Jones R.D.
        • Jones T.H.
        • Channer K.S.
        Testosterone as a protective factor against atherosclerosis—immunomodulation and influence upon plaque development and stability.
        J Endocrinol. 2003; 178: 373-380
        • Libby P.
        Inflammation in atherosclerosis.
        Nature. 2002; 420: 868-874
        • Ross R.
        Atherosclerosis—an inflammatory disease.
        N Engl J Med. 1999; 340: 115-126
        • Norata G.D.
        • Tibolla G.
        • Seccomandi P.M.
        • Poletti A.
        • Catapano A.L.
        Dihydrotestosterone decreases tumor necrosis factor-alpha and lipopolysaccharide-induced inflammatory response in human endothelial cells.
        J Clin Endocrinol Metab. 2006; 91: 546-554
        • Arnal J.F.
        • Scarabin P.Y.
        • Tremollieres F.
        • Laurell H.
        • Gourdy P.
        Estrogens in vascular biology and disease: where do we stand today?.
        Curr Opin Lipidol. 2007; 18: 554-560
        • Weihua Z.
        • Lathe R.
        • Warner M.
        • Gustafsson J.A.
        An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth.
        Proc Natl Acad Sci USA. 2002; 99: 13589-13594
        • Guerini V.
        • Sau D.
        • Scaccianoce E.
        • et al.
        The androgen derivative 5alpha-androstane-3beta,17beta-diol inhibits prostate cancer cell migration through activation of the estrogen receptor beta subtype.
        Cancer Res. 2005; 65: 5445-5453
        • Norata G.D.
        • Pirillo A.
        • Callegari E.
        • Hamsten A.
        • Catapano A.L.
        • Eriksson P.
        Gene expression and intracellular pathways involved in endothelial dysfunction induced by VLDL and oxidised VLDL.
        Cardiovasc Res. 2003; 59: 169-180
        • Pak T.R.
        • Chung W.C.
        • Hinds L.R.
        • Handa R.J.
        Estrogen receptor-beta mediates dihydrotestosterone-induced stimulation of the arginine vasopressin promoter in neuronal cells.
        Endocrinology. 2007; 148: 3371-3382
        • Mishra R.G.
        • Stanczyk F.Z.
        • Burry K.A.
        • et al.
        Metabolite ligands of estrogen receptor-beta reduce primate coronary hyperreactivity.
        Am J Physiol Heart Circ Physiol. 2006; 290: H295-303
        • Norata G.D.
        • Marchesi P.
        • Pirillo A.
        • et al.
        Long pentraxin 3, a key component of innate immunity, is modulated by high-density lipoproteins in endothelial cells.
        Arterioscler Thromb Vasc Biol. 2008; 28: 925-931
        • Norata G.D.
        • Callegari E.
        • Marchesi M.
        • Chiesa G.
        • Eriksson P.
        • Catapano A.L.
        High-density lipoproteins induce transforming growth factor-beta2 expression in endothelial cells.
        Circulation. 2005; 111: 2805-2811
        • Pirillo A.
        • Norata G.D.
        • Zanelli T.
        • Catapano A.L.
        Overexpression of inducible heat shock protein 70 in Cos-1 cells fails to protect from cytotoxicity of oxidized LDLs.
        Arterioscler Thromb Vasc Biol. 2001; 21: 348-354
        • Leon C.G.
        • Locke J.A.
        • Adomat H.H.
        • et al.
        Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model.
        Prostate. 2010; 70: 390-400
        • Laaksonen D.E.
        • Niskanen L.
        • Punnonen K.
        • et al.
        Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men.
        Diabetes Care. 2004; 27: 1036-1041
        • Muller M.
        • van den Beld A.W.
        • Bots M.L.
        • Grobbee D.E.
        • Lamberts S.W.
        • van der Schouw Y.T.
        Endogenous sex hormones and progression of carotid atherosclerosis in elderly men.
        Circulation. 2004; 109: 2074-2079
        • Yeap B.B.
        • Hyde Z.
        • Almeida O.P.
        • et al.
        Lower testosterone levels predict incident stroke and transient ischemic attack in older men.
        J Clin Endocrinol Metab. 2009; 161: 591-598
        • Jones T.H.
        • Saad F.
        The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process.
        Atherosclerosis. 2009; 207: 318-327
        • Traish A.M.
        • Saad F.
        • Feeley R.J.
        • Guay A.
        The dark side of testosterone deficiency: III. Cardiovascular disease.
        J Androl. 2009; 30: 477-494
        • Hatakeyama H.
        • Nishizawa M.
        • Nakagawa A.
        • Nakano S.
        • Kigoshi T.
        • Uchida K.
        Testosterone inhibits tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in human aortic endothelial cells.
        FEBS Lett. 2002; 530: 129-132