Crucial role of androgen receptor in vascular H2S biosynthesis induced by testosterone

Br J Pharmacol. 2015 Mar;172(6):1505-15. doi: 10.1111/bph.12740. Epub 2014 Jul 2.


Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alkynes / pharmacology
  • Androgen Antagonists / pharmacology
  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / metabolism
  • Female
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Humans
  • Hydrogen Sulfide / metabolism*
  • Imidazolidines / pharmacology
  • Male
  • Middle Aged
  • Rats
  • Rats, Wistar
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / metabolism*
  • Sex Factors
  • Testosterone / pharmacology*
  • Vasodilation / drug effects*
  • Vasodilator Agents / pharmacology


  • Alkynes
  • Androgen Antagonists
  • Imidazolidines
  • Receptors, Androgen
  • Vasodilator Agents
  • Testosterone
  • nilutamide
  • propargylglycine
  • Glycine
  • Hydrogen Sulfide