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

Abstract

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.

Keywords: Endothelial cells; Hydrogen sulfide; Metal nonoate; Nitric oxide; Vascular smooth muscle cells.