title: Crucial role of androgen receptor in vascular H2S biosynthesis induced by testosterone.
abstract: OBJECTIVE
  Hydrogen sulphide (H2S) is a gaseous mediator strongly involved in cardiovascular homeostasis, where it provokes vasodilatation. Having previously shown that H2 S contributes to testosterone-induced vasorelaxation, here we aim to uncover the mechanisms underlying this effect.
  
  
  METHODS
  H2 S biosynthesis was evaluated in rat isolated aortic rings following androgen receptor (NR3C4) stimulation. Co-immunoprecipitation and surface plasmon resonance analysis were performed to investigate mechanisms involved in NR3C4 activation.
  
  
  RESULTS
  Pretreatment with NR3C4 antagonist nilutamide prevented testosterone-induced increase in H2S and reduced its vasodilator effect. Androgen agonist mesterolone also increased H2S and induced vasodilatation; effects attenuated by the selective cystathionine-γ lyase (CSE) inhibitor propargylglycine. The NR3C4-multicomplex-derived heat shock protein 90 (hsp90) was also involved in this effect; its specific inhibitor geldanamycin strongly reduced testosterone-induced H2S production. Neither progesterone nor 17-β-oestradiol induced H2S release. Furthermore, we demonstrated that CSE, the main vascular H2S-synthesizing enzyme, is physically associated with the NR3C4/hsp90 complex and the generation of such a ternary system represents a key event leading to CSE activation. Finally, H2S levels in human blood collected from male healthy volunteers were higher than those in female samples.
  
  
  CONCLUSIONS
  We demonstrated that selective activation of the NR3C4 is essential for H2S biosynthesis within vascular tissue, and this event is based on the formation of a ternary complex between cystathionine-γ lyase, NR3C4and hsp90. This novel molecular mechanism operating in the vasculature, corroborated by higher H2S levels in males, suggests that the L-cysteine/CSE/H2S pathway may be preferentially activated in males leading to gender-specific H2S biosynthesis.
authors.affiliation: Department of Science, University of Basilicata, Potenza, Italy; Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Brancaleone
authors.forename: V
authors.initials: V
authors.lastname: Vellecco
authors.forename: D S
authors.initials: DS
authors.lastname: Matassa
authors.forename: R
authors.initials: R
authors.lastname: d'Emmanuele di Villa Bianca
authors.forename: R
authors.initials: R
authors.lastname: Sorrentino
authors.forename: A
authors.initials: A
authors.lastname: Ianaro
authors.forename: M
authors.initials: M
authors.lastname: Bucci
authors.forename: F
authors.initials: F
authors.lastname: Esposito
authors.forename: G
authors.initials: G
authors.lastname: Cirino
mesh_terms: D000328:Adult; D000480:Alkynes / Q000494:pharmacology; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D048289:Imidazolidines / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D012737:Sex Factors; D013739:Testosterone / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000480:Alkynes; D000726:Androgen Antagonists; D048289:Imidazolidines; D011944:Receptors, Androgen; D014665:Vasodilator Agents; D013739:Testosterone; C021277:nilutamide; C009055:propargylglycine; D005998:Glycine; D006862:Hydrogen Sulfide
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