Cross-talk between endogenous H2S and NO accounts for vascular protective activity of the metal-nonoate Zn(PipNONO)Cl

Nitric oxide (NO) and hydrogen sulfide (H2S) are now recognized as gaseous transmitters with many cardiovascular
protective properties. The present study concerns the possibility that NO donors can also function
through endogenous activation of NO and H2S pathways. Based on the previous characterization of a novel
metal-nonoate, Ni(PipNONO)Cl, our aim was: 1) to study the effects of a zinc based compound, Zn(PipNONO)Cl,
on vascular endothelial and smooth muscle cells, and 2) to assess the role and interplay between endogenous NO
and H2S promoted by the nonoate.
Zn(PipNONO)Cl completely reproduced the vasodilation elicited by Ni(PipNONO)Cl. In the presence of endothelium,
preincubation with Zn(PipNONO)Cl sensitized the intima to acetylcholine-induced vasodilation.
When tested on cultured endothelial cells, Zn(PipNONO)Cl prompted PI-3K/Akt- and MAPK/ERK1/2-mediated
survival. Nitrite levels indicated fast NO release (due to the molecule) and delayed (1–6 h) NO production linked
to PI-3K/Akt-dependent eNOS activation. In the same time frame (1–6 h), significant CSE-dependent H2S levels
were detected in response to Zn(PipNONO)Cl. The mechanisms responsible for H2S increase seemed to depend
on the NONO moiety/sGC/cGMP pathway and zinc-associated ROS production. Our results indicate that endogenous
H2S and NO were produced after fast NO release from Zn(PipNONO)Cl, contributing to the vascular
endothelium protective effect. The effect was partially reproduced on smooth muscle cells, where Zn
(PipNONO)Cl inhibited cell proliferation and migration.
In conclusion, vasorelaxant effects, with complementary activities on endothelium and smooth muscle cells,
are elicited by the novel metal-nonoate Zn(PipNONO)Cl.