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


CONCLUSIONS
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.
Laggner
Hilde
H
Centre of Physiology and Pathophysiology, Department of Medical Chemistry, Austria.
Hermann
Marcela
M
Esterbauer
Harald
H
Muellner
Markus K
MK
Exner
Markus
M
Gmeiner
Bernhard Mk
BM
Kapiotis
Stylianos
S
D000603:Amino Acids, Sulfur / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology*; D005260:Female; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014471:Umbilical Veins / Q000187:drug effects / Q000201:enzymology; D014665:Vasodilator Agents / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology
D000603:Amino Acids, Sulfur; D000806:Angiotensin-Converting Enzyme Inhibitors; D017931:DNA Primers; D012333:RNA, Messenger; D014665:Vasodilator Agents; D007703:Peptidyl-Dipeptidase A; D015032:Zinc; D006862:Hydrogen Sulfide