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.

Efficacy of AdipoDren® in Reducing Interleukin-1-Induced Lymphatic Endothelial Hyperpermeability.

Lymphatic leakage can be seen as a detrimental phenomenon associated with fluid retention and deposition as well as gain of weight. Moreover, lymphatic dysfunction is associated with an inflammatory environment and can be a substrate for other health conditions. A number of treatments can ameliorate lymphatic vasculature: natural substances have been used as treatment options particularly suitable for their consolidated effectiveness and safety profile. Here we report the protective effect of AdipoDren®, an association of a series of plant-derived natural complexes, on lymphatic endothelium permeability promoted by interleukin-1 beta (IL-1ß) and the associated molecular mechanisms. AdipoDren® demonstrated a protective effect on dermal lymphatic endothelial cell permeability increased by IL-1ß. Reduced permeability was due to the maintenance of tight junctions and cell-cell localisation of occludin and zonula occludens-1 (ZO-1). Moreover, AdipoDren® reduced the expression of the inflammatory key element cyclooxygenase-2 (COX-2), while not altering the levels of endothelial and inducible nitric oxide synthases (eNOS and iNOS). The upregulation of antioxidant enzymatic systems (catalase and superoxide dismutase-1, SOD-1) and the downregulation of pro-oxidant markers (p22 phox subunit of NADPH oxidase) were also evident. In conclusion, AdipoDren® would be useful to ameliorate conditions of altered lymphatic vasculature and to support the physiological functionality of the lymphatic endothelium.