The novel gaseous vasorelaxant hydrogen sulfide inhibits angiotensin-converting enzyme activity of endothelial cells

Abstract

OBJECTIVE: Beside NO (nitric monoxide) and CO (carbon monoxide), H2S (hydrogen sulfide) has been identified recently as the third gasotransmitter. By acting directly on KATP-channels on smooth muscle cells (SMC) H2S possesses vasorelaxing properties. It has the potential to react with metal ions (i.e. Cu, Fe, Zn) in metalloproteins. Angiotensin-converting enzyme (ACE), responsible for vasoconstriction, is a zinc (Zn) containing enzyme. We therefore hypothesized that H2S may interact with the Zn in the active center of ACE, modulating (inhibiting) enzyme activity. METHODS: ACE activity was measured on the surface of human endothelial cells (HUVECs) monolayers in culture, ex-vivo in umbilical veins and in HUVEC protein extracts. Quantitative real-time polymerase chain reaction (PCR) was used to study the effect of H2S on ACE mRNA expression in HUVECs. RESULTS: H2S inhibited the activity of ACE in HUVEC protein extracts in a dose-dependent manner, and only Zn but not Cd, Ca or Mg could counteract the inhibitory effect. Cell-surface ACE activity was inhibited by H2S on HUVEC monolayers and in ex-vivo umbilical veins. No influence of H2S on ACE mRNA expression was observed. CONCLUSION: H2S exhibits direct inhibitory action on ACE activity in HUVECs, obviously by interfering with the Zn in the active center of the enzyme. Thus, beside the known influence of H2S on SMC KATP-channels, the observed direct ACE inhibitory effect may add to the vasorelaxant effect of H2S in the vasculature by reducing angiotensin II production and inhibiting bradykinin degradation.